Volume 176, Issue S1 p. S21-S141
THE CONCISE GUIDE TO PHARMACOLOGY 2019/20
Open Access

THE CONCISE GUIDE TO PHARMACOLOGY 2019/20: G protein-coupled receptors

Stephen P H Alexander

Stephen P H Alexander

School of Life Sciences, University of Nottingham Medical School, Nottingham, NG7 2UH UK

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Arthur Christopoulos

Arthur Christopoulos

Monash Institute of Pharmaceutical Sciences and Department of Pharmacology, Monash University, Parkville, Victoria, 3052 Australia

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Anthony P Davenport

Anthony P Davenport

Clinical Pharmacology Unit, University of Cambridge, Cambridge, CB2 0QQ UK

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Eamonn Kelly

Eamonn Kelly

School of Physiology, Pharmacology and Neuroscience, University of Bristol, Bristol, BS8 1TD UK

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Alistair Mathie

Alistair Mathie

Medway School of Pharmacy, The Universities of Greenwich and Kent at Medway, Anson Building, Central Avenue, Chatham Maritime, Chatham, Kent, ME4 4TB UK

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John A Peters

John A Peters

Neuroscience Division, Medical Education Institute, Ninewells Hospital and Medical School, University of Dundee, Dundee, DD1 9SY UK

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Emma L Veale

Emma L Veale

Medway School of Pharmacy, The Universities of Greenwich and Kent at Medway, Anson Building, Central Avenue, Chatham Maritime, Chatham, Kent, ME4 4TB UK

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Jane F Armstrong

Jane F Armstrong

Centre for Discovery Brain Sciences, University of Edinburgh, Edinburgh, EH8 9XD UK

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Elena Faccenda

Elena Faccenda

Centre for Discovery Brain Sciences, University of Edinburgh, Edinburgh, EH8 9XD UK

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Simon D Harding

Simon D Harding

Centre for Discovery Brain Sciences, University of Edinburgh, Edinburgh, EH8 9XD UK

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Adam J Pawson

Adam J Pawson

Centre for Discovery Brain Sciences, University of Edinburgh, Edinburgh, EH8 9XD UK

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Joanna L Sharman

Joanna L Sharman

Centre for Discovery Brain Sciences, University of Edinburgh, Edinburgh, EH8 9XD UK

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Christopher Southan

Christopher Southan

Centre for Discovery Brain Sciences, University of Edinburgh, Edinburgh, EH8 9XD UK

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Jamie A Davies

Jamie A Davies

Centre for Discovery Brain Sciences, University of Edinburgh, Edinburgh, EH8 9XD UK

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CGTP Collaborators
First published: 11 November 2019
Citations: 505

Abstract

The Concise Guide to PHARMACOLOGY 2019/20 is the fourth in this series of biennial publications. The Concise Guide provides concise overviews of the key properties of nearly 1800 human drug targets with an emphasis on selective pharmacology (where available), plus links to the open access knowledgebase source of drug targets and their ligands (www.guidetopharmacology.org), which provides more detailed views of target and ligand properties. Although the Concise Guide represents approximately 400 pages, the material presented is substantially reduced compared to information and links presented on the website. It provides a permanent, citable, point-in-time record that will survive database updates. The full contents of this section can be found at http://onlinelibrary.wiley.com/doi/10.1111/bph.14748. G protein-coupled receptors are one of the six major pharmacological targets into which the Guide is divided, with the others being: ion channels, nuclear hormone receptors, catalytic receptors, enzymes and transporters. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. The landscape format of the Concise Guide is designed to facilitate comparison of related targets from material contemporary to mid-2019, and supersedes data presented in the 2017/18, 2015/16 and 2013/14 Concise Guides and previous Guides to Receptors and Channels. It is produced in close conjunction with the International Union of Basic and Clinical Pharmacology Committee on Receptor Nomenclature and Drug Classification (NC-IUPHAR), therefore, providing official IUPHAR classification and nomenclature for human drug targets, where appropriate.

Conflict of interest

The authors state that there are no conflicts of interest to disclose.

Overview

G protein-coupled receptors (GPCRs) are the largest class of membrane proteins in the human genome. The term "7TM receptor" is commonly used interchangeably with "GPCR", although there are some receptors with seven transmembrane domains that do not signal through G proteins. GPCRs share a common architecture, each consisting of a single polypeptide with an extracellular N-terminus, an intracellular C-terminus and seven hydrophobic transmembrane domains (TM1-TM7) linked by three extracellular loops (ECL1-ECL3) and three intracellular loops (ICL1-ICL3). About 800 GPCRs have been identified in man, of which about half have sensory functions, mediating olfaction (˜400), taste (33), light perception (10) and pheromone signalling (5) [1479]. The remaining 350 non-sensory GPCRs mediate signalling by ligands that range in size from small molecules to peptides to large proteins; they are the targets for the majority of drugs in clinical usage [1642, 1772], although only a minority of these receptors are exploited therapeutically. The first classification scheme to be proposed for GPCRs [1129] divided them, on the basic of sequence homology, into six classes. These classes and their prototype members were as follows: Class A (rhodopsin-like), Class B (secretin receptor family), Class C (metabotropic glutamate), Class D (fungal mating pheromone receptors), Class E (cyclic AMP receptors) and Class F (frizzled/smoothened). Of these, classes D and E are not found in vertebrates. An alternative classification scheme "GRAFS" [1890] divides vertebrate GPCRs into five classes, overlapping with the A-F nomenclature, viz:

Glutamate family (class C), which includes metabotropic glutamate receptors, a calcium-sensing receptor and GABAB receptors, as well as three taste type 1 receptors and a family of pheromone receptors (V2 receptors) that are abundant in rodents but absent in man [1479].

Rhodopsin family (class A), which includes receptors for a wide variety of small molecules, neurotransmitters, peptides and hormones, together with olfactory receptors, visual pigments, taste type 2 receptors and five pheromone receptors (V1 receptors).

Adhesion family GPCRs are phylogenetically related to class B receptors, from which they differ by possessing large extracellular N-termini that are autoproteolytically cleaved from their 7TM domains at a conserved "GPCR proteolysis site" (GPS) which lies within a much larger (320 residue) "GPCR autoproteolysis-inducing" (GAIN) domain, an evolutionary ancient mofif also found in polycystic kidney disease 1 (PKD1)-like proteins, which has been suggested to be both required and sufficient for autoproteolysis [1743].

Frizzled family consists of 10 Frizzled proteins (FZD(1-10)) and Smoothened (SMO). The FZDs are activated by secreted lipoglycoproteins of the WNT family, whereas SMO is indirectly activated by the Hedgehog (HH) family of proteins acting on the transmembrane protein Patched (PTCH).

Secretin family, encoded by 15 genes in humans. The ligands for receptors in this family are polypeptide hormones of 27-141 amino acid residues; nine of the mammalian receptors respond to ligands that are structurally related to one another (glucagon, glucagon-like peptides (GLP-1, GLP-2), glucose-dependent insulinotropic polypeptide (GIP), secretin, vasoactive intestinal peptide (VIP), pituitary adenylate cyclase-activating polypeptide (PACAP) and growth-hormone-releasing hormone (GHRH)) [811].

GPCR families

Family Class A Class B (Secretin) Class C (Glutamate) Adhesion Frizzled
Receptors with known ligands 197 15 12 0 11
Orphans 87 (54)a - 8 (1)a 26 (6)a 0
Sensory (olfaction) 390b,c - - - -
Sensory (vision) 10d opsins - - - -
Sensory (taste) 30c taste 2 - 3c taste 1 - -
Sensory (pheromone) 5c vomeronasal 1 - - - -
Total 719 15 22 33 11

aNumbers in brackets refer to orphan receptors for which an endogenous ligand has been proposed in at least one publication, see [455]; b[1634]; c[1479]; d[2109].

Much of our current understanding of the structure and function of GPCRs is the result of pioneering work on the visual pigment rhodopsin and on the β2 adrenoceptor, the latter culminating in the award of the 2012 Nobel Prize in chemistry to Robert Lefkowitz and Brian Kobilka [1121, 1244].

Pseudogenes

Below is a curated list of pseudogenes that in humans are non-coding for receptor protein. In some cases these have a shared ancestry with genes that encode functional receptors in rats and mice.

ADGRE4P, GNRHR2, GPR79, HTR5BP, NPY6R, TAAR3P, TAAR4P, TAAR7P, TAS2R12P, TAS2R15P, TAS2R18P, TAS2R2P, TAS2R62P, TAS2R63P, TAS2R64P, TAS2R67P, TAS2R68P, TAS2R6P. A more detailed listing containg further information can be viewed here.

Olfactory receptors

Olfactory receptors are also seven-transmembrane spanning G protein-coupled receptors, responsible for the detection of odorants. These are not currently included as they are not yet associated with extensive pharmacological data but are curated in the following databases: The gene list of olfactory receptors at HGNC, and curated by HORDE and ORDB.

Further reading on G protein-coupled receptors

Kenakin T. (2018) Is the Quest for Signaling Bias Worth the Effort? Mol. Pharmacol. 93: 266-269 [PMID:29348268]

Michel MC et al. (2018) Biased Agonism in Drug Discovery-Is It Too Soon to Choose a Path? Mol. Pharmacol. 93: 259-265 [PMID:29326242]

Roth BL et al. (2017) Discovery of new GPCR ligands to illuminate new biology. Nat. Chem. Biol. 13: 1143-1151 [PMID:29045379]

Sriram K et al. (2018) G Protein-Coupled Receptors as Targets for Approved Drugs: How Many Targets and How Many Drugs? Mol. Pharmacol. 93: 251-258 [PMID:29298813]

Family structure

S23 Orphan and other 7TM receptors

S24 Class A Orphans

Class B Orphans

S33 Class C Orphans

Opsin receptors

S33 Taste 1 receptors

S34 Taste 2 receptors

S35 Other 7TM proteins

S36 5-Hydroxytryptamine receptors

S39 Acetylcholine receptors (muscarinic)

S41 Adenosine receptors

S42 Adhesion Class GPCRs

S45 Adrenoceptors

S48 Angiotensin receptors

S50 Apelin receptor

S51 Bile acid receptor

S51 Bombesin receptors

S53 Bradykinin receptors

S54 Calcitonin receptors

S56 Calcium-sensing receptor

S57 Cannabinoid receptors

S58 Chemerin receptors

S59 Chemokine receptors

S63 Cholecystokinin receptors

S64 Class Frizzled GPCRs

S67 Complement peptide receptors

S68 Corticotropin-releasing factor receptors

S69 Dopamine receptors

S71 Endothelin receptors

S72 G protein-coupled estrogen receptor

S73 Formylpeptide receptors

S74 Free fatty acid receptors

S76 GABAB receptors

S78 Galanin receptors

S79 Ghrelin receptor

S80 Glucagon receptor family

S81 Glycoprotein hormone receptors

S82 Gonadotrophin-releasing hormone receptors

S83 GPR18, GPR55 and GPR119

S84 Histamine receptors

S86 Hydroxycarboxylic acid receptors

S87 Kisspeptin receptor

S88 Leukotriene receptors

S89 Lysophospholipid (LPA) receptors

S90 Lysophospholipid (S1P) receptors

S92 Melanin-concentrating hormone receptors

S93 Melanocortin receptors

S94 Melatonin receptors

S95 Metabotropic glutamate receptors

S97 Motilin receptor

S98 Neuromedin U receptors

S99 Neuropeptide FF/neuropeptide AF receptors

S100 Neuropeptide S receptor

S101 Neuropeptide W/neuropeptide B receptors

S102 Neuropeptide Y receptors

S103 Neurotensin receptors

S104 Opioid receptors

S106 Orexin receptors

S107 Oxoglutarate receptor

S108 P2Y receptors

S110 Parathyroid hormone receptors

S111 Platelet-activating factor receptor

S112 Prokineticin receptors

S113 Prolactin-releasing peptide receptor

S114 Prostanoid receptors

S116 Proteinase-activated receptors

S117 QRFP receptor

S118 Relaxin family peptide receptors

S120 Somatostatin receptors

S121 Succinate receptor

S122 Tachykinin receptors

S123 Thyrotropin-releasing hormone receptors

S124 Trace amine receptor

S125 Urotensin receptor

S126 Vasopressin and oxytocin receptors

S127 VIP and PACAP receptors

Orphan and other 7TM receptors

Overview

This set contains ’orphan’ G protein coupled receptors where the endogenous ligand(s) is not known, and other 7TM receptors.

Class A Orphans

Overview

Table 1 lists a number of putative GPCRs identified by NC-IUPHAR[612], for which preliminary evidence for an endogenous ligand has been published, or for which there exists a potential link to a disease, or disorder. These GPCRs have recently been reviewed in detail [455]. The GPCRs in Table 1 are all Class A, rhodopsin-like GPCRs. Class A orphan GPCRs not listed in Table 1 are putative GPCRs with as-yet unidentified endogenous ligands.

Table 1

Class A orphan GPCRs with putative endogenous ligands

GPR3 GPR4 GPR6 GPR12 GPR15 GPR17 GPR20
GPR22 GPR26 GPR31 GPR34 GPR35 GPR37 GPR39
GPR50 GPR63 GRP65 GPR68 GPR75 GPR84 GPR87
GPR88 GPR132 GPR149 GPR161 GPR183 LGR4 LGR5
LGR6 MAS1 MRGPRD MRGPRX1 MRGPRX2 P2RY10 TAAR2

In addition the orphan receptors GPR18, GPR55 and GPR119 which are reported to respond to endogenous agents analogous to the endogenous cannabinoid ligands have been grouped together (GPR18, GPR55 and GPR119).

Nomenclature GPR3 GPR4 GPR6
HGNC, UniProt GPR3, P46089 GPR4, P46093 GPR6, P46095
Agonists diphenyleneiodonium chloride [2388]
Endogenous ligands Protons
Comments Sphingosine 1-phosphate was reported to be an endogenous agonist [2168], but this finding was not replicated in subsequent studies [2389]. Reported to activate adenylyl cyclase constitutively through Gs [545]. Gene disruption results in premature ovarian ageing [1234], reduced β-amyloid deposition [2112] and hypersensitivity to thermal pain [1837] in mice. First small molecule inverse agonist [993] and agonists identified [2386] An initial report suggesting activation by lysophosphatidylcholine and sphingosylphosphorylcholine [2440] has been retracted [1597]. GPR4, GPR65, GPR68 and GPR132 are now thought to function as proton-sensing receptors detecting acidic pH [455, 1932]. Gene disruption is associated with increased perinatal mortality and impaired vascular proliferation [2377]. Negative allosteric modulators of GPR4 have been reported [2137]. An initial report that sphingosine 1-phosphate (S1P) was a high-affinity ligand (EC50 value of 39nM) [941, 2168] was not repeated in arrestin-based assays [2017, 2389]. Reported to activate adenylyl cyclase constitutively through Gs and to be located intracellularly [1644]. GPR6-deficient mice showed reduced striatal cyclic AMP production in vitro and selected alterations in instrumental conditioning in vivo. [1309].
Nomenclature GPR12 GPR15 GPR17
HGNC, UniProt GPR12, P47775 GPR15, P49685 GPR17, Q13304
Endogenous agonists UDP-glucose [143, 395], LTC4 [395], UDP-galactose [143, 395], uridine diphosphate [143, 395], LTD4[395]
Comments Reports that sphingosine 1-phosphate is a ligand of GPR12 [940, 2168] have not been replicated in arrestin-based assays [2015, 2389]. Gene disruption results in dyslipidemia and obesity [170]. Reported to act as a co-receptor for HIV [541]. In an infection-induced colitis model, Gpr15 knockout mice were more prone to tissue damage and inflammatory cytokine expression [1089]. Reported to be a dual leukotriene and uridine diphosphate receptor [395]. Another group instead proposed that GPR17 functions as a negative regulator of the CysLT1 receptor response to leukotriene D4 (LTD4). For further discussion, see [455]. Reported to antagonize CysLT1 receptor signalling in vivo and in vitro [1350]. See reviews [280] and [455].
Nomenclature GPR19 GPR20 GPR21 GPR22 GPR25 GPR26 GPR27
HGNC, UniProt GPR19, Q15760 GPR20, Q99678 GPR21, Q99679 GPR22, Q99680 GPR25, O00155 GPR26, Q8NDV2 GPR27, Q9NS67
Agonists adropin (ENHO, Q6UWT2) [1770]
Comments Reported to inhibit adenylyl cyclase constitutively through Gi/o [817]. GPR20 deficient mice exhibit hyperactivity characterised by increased total distance travelled in an open field test [230]. Gpr21 knockout mice were resistant to diet-induced obesity, exhibiting an increase in glucose tolerance and insulin sensitivity, as well as a modest lean phenotype [1639]. Gene disruption results in increased severity of functional decompensation following aortic banding [10]. Identified as a susceptibility locus for osteoarthritis [574, 1072, 2187]. Has been reported to activate adenylyl cyclase constitutively through Gs [1016]. Gpr26 knockout mice show increased levels of anxiety and depression-like behaviours [2421]. Knockdown of Gpr27 reduces endogenous mouse insulin promotor activity and glucose-stimulated insulin secretion [1160].
Nomenclature GPR31 GPR32 GPR33 GPR34
HGNC, UniProt GPR31, O00270 GPR32, O75388 GPR33, Q49SQ1 GPR34, Q9UPC5
Potency order of endogenous ligands resolvin D1 > LXA4
Endogenous agonists 12S-HETE [769] – Mouse resolvin D1 [1153], LXA4 [1153] lysophosphatidylserine [1107, 2054]
Labelled ligands [3H]resolvin D1 (Agonist) [1153]
Comments See [455] for discussion of pairing. Resolvin D1 has been demonstrated to activate GPR32 in two publications [366, 1153]. The pairing was not replicated in a recent study based on arrestin recruitment [2015]. GPR32 is a pseudogene in mice and rats. See reviews [280] and [455]. GPR33 is a pseudogene in most individuals, containing a premature stop codon within the coding sequence of the second intracellular loop [1845]. Lysophosphatidylserine has been reported to be a ligand of GPR34 in several publications, but the pairing was not replicated in a recent study based on arrestin recruitment [2015]. Fails to respond to a variety of lipid-derived agents [2389]. Gene disruption results in an enhanced immune response [1277]. Characterization of agonists at this receptor is discussed in [945] and [455].
Nomenclature GPR35 GPR37
HGNC, UniProt GPR35, Q9HC97 GPR37, O15354
Endogenous agonists 2-oleoyl-LPA [1626], kynurenic acid [2015, 2253]
Agonists neuropeptide head activator [1795]
Comments Several studies have shown that kynurenic acid is an agonist of GPR35 but it remains controversial whether the proposed endogenous ligand reaches sufficient tissue concentrations to activate the receptor [1162]. 2-oleoyl-LPA has also been proposed as an endogenous ligand [1626] but these results were not replicated in an arrestin assay [2015]. The phosphodiesterase inhibitor zaprinast [2105] has become widely used as a surrogate agonist to investigate GPR35 pharmacology and signalling [2105]. GPR35 is also activated by the pharmaceutical adjunct pamoic acid [2432]. See reviews [455] and [502]. Reported to associate and regulate the dopamine transporter [1382] and to be a substrate for parkin [1380]. Gene disruption results in altered striatal signalling [1381]. The peptides prosaptide and prosaposin are proposed as endogenous ligands for GPR37 and GPR37L1 [1438].
Nomenclature GPR37L1 GPR39 GPR45 GPR50
HGNC, UniProt GPR37L1, O60883 GPR39, O43194 GPR45, Q9Y5Y3 GPR50, Q13585
Endogenous agonists Zn2+ [898]
Comments The peptides prosaptide and prosaposin are proposed as endogenous ligands for GPR37 and GPR37L1 [1438]. Zn2+ has been reported to be a potent and efficacious agonist of human, mouse and rat GPR39 [2383]. Obestatin (GHRL, Q9UBU3), a fragment from the ghrelin precursor, was reported initially as an endogenous ligand, but subsequent studies failed to reproduce these findings. GPR39 has been reported to be down-regulated in adipose tissue in obesity-related diabetes [315]. Gene disruption results in obesity and altered adipocyte metabolism [1696]. Reviewed in [455]. GPR50 is structurally related to MT1 and MT2 melatonin receptors, with which it heterodimerises constitutively and specifically [1265]. Gpr50 knockout mice display abnormal thermoregulation and are much more likely than wild-type mice to enter fasting-induced torpor [126].
Nomenclature GPR52 GPR61 GPR62 GPR63
HGNC, UniProt GPR52, Q9Y2T5 GPR61, Q9BZJ8 GPR62, Q9BZJ7 GPR63, Q9BZJ6
Comments First small molecule agonist reported [1931]. GPR61 deficient mice exhibit obesity associated with hyperphagia [1545]. Although no endogenous ligands have been identified, 5-(nonyloxy)tryptamine has been reported to be a low affinity inverse agonist [2092]. Sphingosine 1-phosphate and dioleoylphosphatidic acid have been reported to be low affinity agonists for GPR63 [1584] but this finding was not replicated in an arrestin-based assay [2389].
Nomenclature GPR65 GPR68
HGNC, UniProt GPR65, Q8IYL9 GPR68, Q15743
Endogenous ligands Protons Protons
Allosteric modulators ogerin (Positive) (pKB 5) [925], lorazepam (Positive) [925]
Comments GPR4, GPR65, GPR68 and GPR132 are now thought to function as proton-sensing receptors detecting acidic pH [455, 1932]. Reported to activate adenylyl cyclase; gene disruption leads to reduced eosinophilia in models of allergic airway disease [1145]. GPR68 was previously identified as a receptor for sphingosylphosphorylcholine (SPC) [2358], but the original publication has been retracted [2357]. GPR4, GPR65, GPR68 and GPR132 are now thought to function as proton-sensing receptors detecting acidic pH [455, 1932]. A family of 3,5-disubstituted isoxazoles were identified as agonists of GPR68 [1839].
Nomenclature GPR75 GPR78 GPR79 GPR82
HGNC, UniProt GPR75, O95800 GPR78, Q96P69 GPR79, – GPR82, Q96P67
Comments CCL5(CCL5, P13501) was reported to be an agonist of GPR75 [942], but the pairing could not be repeated in an arrestin assay [2015]. GPR78 has been reported to be constitutively active, coupled to elevated cAMP production [1016]. Mice with Gpr82 knockout have a lower body weight and body fat content associated with reduced food intake, decreased serum triglyceride levels, as well as higher insulin sensitivity and glucose tolerance [558].
Nomenclature GPR83 GPR84 GPR85 GPR87 GPR88 GPR101
HGNC, UniProt GPR83, Q9NYM4 GPR84, Q9NQS5 GPR85, P60893 GPR87, Q9BY21 GPR88, Q9GZN0 GPR101, Q96P66
Endogenous agonists LPA [1523, 2076]
Agonists PEN {Mouse} [719] – Mouse, Zn2+ [1531] – Mouse decanoic acid [2015, 2254], undecanoic acid[2254], lauric acid[2254]
Comments One isoform has been implicated in the induction of CD4(+) CD25(+) regulatory T cells (Tregs) during inflammatory immune responses [803]. The extracellular N-terminal domain is reported as an intramolecular inverse agonist [1532]. Medium chain free fatty acids with carbon chain lengths of 9-14 activate GPR84 [2064, 2254]. A surrogate ligand for GPR84, 6-n-octylaminouracil has also been proposed [2064]. See review [455] for discussion of classification. Mutational analysis and molecular modelling of GPR84 has been reported [1588]. Proposed to regulate hippocampal neurogenesis in the adult, as well as neurogenesis-dependent learning and memory [352]. Gene disruption results in altered striatal signalling [1312]. Small molecule agonists have been reported [163]. Mutations in GPR101 have been linked to gigantism and acromegaly [2154].
Nomenclature GPR132 GPR135 GPR139 GPR141 GPR142 GPR146
HGNC, UniProt GPR132, Q9UNW8 GPR135, Q8IZ08 GPR139, Q6DWJ6 GPR141, Q7Z602 GPR142, Q7Z601 GPR146, Q96CH1
Endogenous ligands Protons
Comments GPR4, GPR65, GPR68 and GPR132 are now thought to function as proton-sensing receptors detecting acidic pH [455, 1932]. Reported to respond to lysophosphatidylcholine [1027], but later retracted [2321]. Peptide agonists have been reported [953]. Small molecule agonists have been reported [2138, 2407]. Yosten et al. demonstrated inhibition of proinsulin C-peptide (INS, P01308)-induced stimulation of cFos expression folllowing knockdown of GPR146 in KATO III cells, suggesting proinsulin C-peptide as an endogenous ligand of the receptor [2404].
Nomenclature GPR148 GPR149 GPR150 GPR151 GPR152 GPR153 GPR160
HGNC, UniProt GPR148, Q8TDV2 GPR149, Q86SP6 GPR150, Q8NGU9 GPR151, Q8TDV0 GPR152, Q8TDT2 GPR153, Q6NV75 GPR160, Q9UJ42
Comments Gpr149 knockout mice displayed increased fertility and enhanced ovulation, with increased levels of FSH receptor and cyclin D2 mRNA levels [542]. GPR151 responded to galanin with an EC50 value of 2 μM, suggesting that the endogenous ligand shares structural features with galanin (GAL, P22466) [939].
Nomenclature GPR161 GPR162 GPR171 GPR173
HGNC, UniProt GPR161, Q8N6U8 GPR162, Q16538 GPR171, O14626 GPR173, Q9NS66
Comments A C-terminal truncation (deletion) mutation in Gpr161 causes congenital cataracts and neural tube defects in the vacuolated lens (vl) mouse mutant [1403]. The mutated receptor is associated with cataract, spina bifida and white belly spot phenotypes in mice [1140]. Gene disruption is associated with a failure of asymmetric embryonic development in zebrafish [1261]. GPR171 has been shown to be activated by the endogenous peptide BigLEN {Mouse}. This receptor-peptide interaction is believed to be involved in regulating feeding and metabolism responses [718].
Nomenclature GPR174 GPR176 GPR182 GPR183
HGNC, UniProt GPR174, Q9BXC1 GPR176, Q14439 GPR182, O15218 GPR183, P32249
Endogenous agonists lysophosphatidylserine [949] 7α,25-dihydroxycholesterol [799, 1301], 7α,27-dihydroxycholesterol[1301], 7β, 25-dihydroxycholesterol[1301], 7β, 27-dihydroxycholesterol[1301]
Comments See [945] which discusses characterization of agonists at this receptor. Rat GPR182 was first proposed as the adrenomedullin receptor [1041]. However, it was later reported that rat and human GPR182 did not respond to adrenomedullin [1070] and GPR182 is not currently considered to be a genuine adrenomedullin receptor [831]. Two independent publications have shown that 7α,25-dihydroxycholesterol is an agonist of GPR183 and have demonstrated by mass spectrometry that this oxysterol is present endogenously in tissues [799, 1301]. Gpr183-deficient mice show a reduction in the early antibody response to a T-dependent antigen. GPR183-deficient B cells fail to migrate to the outer follicle and instead stay in the follicle centre [1062, 1685].
Nomenclature LGR4 LGR5 LGR6
HGNC, UniProt LGR4, Q9BXB1 LGR5, O75473 LGR6, Q9HBX8
Endogenous agonists R-spondin-2 (RSPO2, Q6UXX9) [305], R-spondin-1 (RSPO1, Q2MKA7) [305], R-spondin-3 (RSPO3, Q9BXY4) [305], R-spondin-4 (RSPO4, Q2I0M5) [305] R-spondin-2 (RSPO2, Q6UXX9) [305], R-spondin-1 (RSPO1, Q2MKA7) [305], R-spondin-3 (RSPO3, Q9BXY4) [305], R-spondin-4 (RSPO4, Q2I0M5) [305] R-spondin-1 (RSPO1, Q2MKA7) [305, 467], R-spondin-2 (RSPO2, Q6UXX9) [305, 467], R-spondin-3 (RSPO3, Q9BXY4) [305, 467], R-spondin-4 (RSPO4, Q2I0M5) [305, 467]
Comments LGR4 does not couple to heterotrimeric G proteins or recruit arrestins when stimulated by the R-spondins, indicating a unique mechanism of action. R-spondins bind to LGR4, which specifically associates with Frizzled and LDL receptor-related proteins (LRPs) that are activated by the extracellular Wnt molecules and then trigger canonical Wnt signalling to increase gene expression [305, 467, 1834]. Gene disruption leads to multiple developmental disorders [1002, 1329, 2011, 2284]. The four R-spondins can bind to LGR4, LGR5, and LGR6, which specifically associate with Frizzled and LDL receptor-related proteins (LRPs), proteins that are activated by extracellular Wnt molecules and which then trigger canonical Wnt signalling to increase gene expression [305, 467].
Nomenclature MAS1 MAS1L
HGNC, UniProt MAS1, P04201 MAS1L, P35410
Agonists angiotensin-(1-7) (AGT, P01019) [707] – Mouse
Nomenclature MRGPRD MRGPRE MRGPRF MRGPRG
HGNC, UniProt MRGPRD, Q8TDS7 MRGPRE, Q86SM8 MRGPRF, Q96AM1 MRGPRG, Q86SM5
Endogenous agonists β-alanine [1958, 2015]
Comments An endogenous peptide with a high degree of sequence similarity to angiotensin-(1-7) (AGT, P01019), alamandine (AGT), was shown to promote NO release in MRGPRD-transfected cells. The binding of alamandine to MRGPRD to was shown to be blocked by D-Pro7-angiotensin-(1-7), β-alanine and PD123319 [1208]. Genetic ablation of MRGPRD+ neurons of adult mice decreased behavioural sensitivity to mechanical stimuli but not to thermal stimuli [322]. See reviews [455] and [2009]. See reviews [455] and [2009]. MRGPRF has been reported to respond to stimulation by angiotensin metabolites [678]. See reviews [455] and [2009]. See reviews [455] and [2009].
Nomenclature MRGPRX1 MRGPRX2 MRGPRX3 MRGPRX4 P2RY8 P2RY10
HGNC, UniProt MRGPRX1, Q96LB2 MRGPRX2, Q96LB1 MRGPRX3, Q96LB0 MRGPRX4, Q96LA9 P2RY8, Q86VZ1 P2RY10, O00398
Endogenous agonists bovine adrenal medulla peptide 8-22 (PENK, P01210) [347, 1253, 2015] PAMP-20 (ADM, P35318) [1035] sphingosine 1-phosphate [1523], LPA [1523]
Agonists cortistatin-14 {Mouse, Rat} [1035, 1202, 1815, 2015]
Selective agonists PAMP-12 (human) [1035]
Comments Reported to mediate the sensation of itch [1305, 1969]. Reports that bovine adrenal medulla peptide 8-22 (PENK, P01210) was the most potent of a series of proenkephalin A-derived peptides as an agonist of MRGPRX1 in assays of calcium mobilisation and radioligand binding [1253] were replicated in an independent study using an arrestin recruitment assay [2015]. See reviews [455] and [2009]. A diverse range of substances has been reported to be agonists of MRGPRX2, with cortistatin 14 the highest potency agonist in assays of calcium mobilisation [1815], also confirmed in an independent study using an arrestin recruitment assay [2015]. See reviews [455] and [2009]. See reviews [455] and [2009].
Nomenclature TAAR2 TAAR3 TAAR4P TAAR5 TAAR6 TAAR8 TAAR9
HGNC, UniProt TAAR2, Q9P1P5 TAAR3P, Q9P1P4 TAAR4P, – TAAR5, O14804 TAAR6, Q96RI8 TAAR8, Q969N4 TAAR9, Q96RI9
Potency order of endogenous ligands β-phenylethylamine > tryptamine [205]
Comments Probable pseudogene in 10–15% of Asians due to a polymorphism (rs8192646) producing a premature stop codon at amino acid 168 [455]. TAAR3 is thought to be a pseudogene in man though functional in rodents [455]. Pseudogene in man but functional in rodents [455]. Trimethylamine is reported as an agonist [2242] and 3-iodothyronamine an inverse agonist [499]. TAAR9 appears to be functional in most individuals but has a polymorphic premature stop codon at amino acid 61 (rs2842899) with an allele frequency of 10–30% in different populations [2202].

Further reading on Class A Orphans

McNeil BD et al. (2015) Identification of a mast-cell-specific receptor crucial for pseudo-allergic drug reactions. Nature 519: 237–41 [PMID:25517090]

Class C Orphans

Overview

This set contains class C ’orphan’ G protein coupled receptors where the endogenous ligand(s) is not known.

Nomenclature GPR156 GPR158 GPR179 GPRC5A GPRC5B GPRC5C GPRC5D GPRC6 receptor
HGNC, UniProt GPR156, Q8NFN8 GPR158, Q5T848 GPR179, Q6PRD1 GPRC5A, Q8NFJ5 GPRC5B, Q9NZH0 GPRC5C, Q9NQ84 GPRC5D, Q9NZD1 GPRC6A, Q5T6X5
Comments GPRC6 is a Gq-coupled receptor which responds to basic amino acids [2282].

Further reading on Class C Orphans

Harpse K et al. (2017) Structural insight to mutation effects uncover a common allosteric site in class C GPCRs. Bioinformatics 33: 1116–1120 [PMID:28011766]

Taste 1 receptors

Overview

Whilst the taste of acid and salty foods appear to be sensed by regulation of ion channel activity, bitter, sweet and umami tastes are sensed by specialised GPCR. Two classes of taste GPCR have been identified, T1R and T2R, which are similar in sequence and structure to Class C and Class A GPCR, respectively. Activation of taste receptors appears to involve gustducin- (Gαt3) and Gα14-mediated signalling, although the precise mechanisms remain obscure. Gene disruption studies suggest the involvement of PLCβ2 [2429], TRPM5 [2429] and IP3 [883] receptors in postreceptor signalling of taste receptors. Although predominantly associated with the oral cavity, taste receptors are also located elsewhere, including further down the gastrointestinal system, in the lungs and in the brain.

Sweet/Umami

T1R3 acts as an obligate partner in T1R1/T1R3 and T1R2/T1R3 heterodimers, which sense umami or sweet, respectively. T1R1/T1R3 heterodimers respond to L-glutamic acid and may be positively allosterically modulated by 5’-nucleoside monophosphates, such as 5’-GMP [1272]. T1R2/T1R3 heterodimers respond to sugars, such as sucrose, and artificial sweeteners, such as saccharin [1564].

Nomenclature TAS1R1 TAS1R2 TAS1R3
HGNC, UniProt TAS1R1, Q7RTX1 TAS1R2, Q8TE23 TAS1R3, Q7RTX0

Comments

Positive allosteric modulators of T1R2/T1R3 have been reported [2363]. Such compounds enhance the sweet taste of sucrose mediated by these receptors, but are tasteless on their own.

Further reading on Taste 1 receptors

Palmer RK. (2019) A Pharmacological Perspective on the Study of Taste. Pharmacol. Rev. 71: 20–48 [PMID:30559245]

Taste 2 receptors

G protein-coupled receptors → Orphan and other 7TM receptors → Taste 2 receptors

Overview

The composition and stoichiometry of bitter taste receptors is not yet established. Bitter receptors appear to separate into two groups, with very restricted ligand specificity or much broader responsiveness. For example, T2R5 responded to cycloheximide, but not 10 other bitter compounds [334], while T2R14 responded to at least eight different bitter tastants, including (-)-α-thujone and picrotoxinin [133].

Specialist database BitterDB contains additional information on bitter compounds and receptors [2306].

Nomenclature TAS2R1 TAS2R3 TAS2R4 TAS2R5 TAS2R7 TAS2R8 TAS2R9
HGNC, UniProt TAS2R1, Q9NYW7 TAS2R3, Q9NYW6 TAS2R4, Q9NYW5 TAS2R5, Q9NYW4 TAS2R7, Q9NYW3 TAS2R8, Q9NYW2 TAS2R9, Q9NYW1
Nomenclature TAS2R10 TAS2R13 TAS2R14 TAS2R16 TAS2R19 TAS2R20 TAS2R30
HGNC, UniProt TAS2R10, Q9NYW0 TAS2R13, Q9NYV9 TAS2R14, Q9NYV8 TAS2R16, Q9NYV7 TAS2R19, P59542 TAS2R20, P59543 TAS2R30, P59541
Nomenclature TAS2R31 TAS2R38 TAS2R39 TAS2R40
HGNC, UniProt TAS2R31, P59538 TAS2R38, P59533 TAS2R39, P59534 TAS2R40, P59535
Antagonists 6-methoxysakuranetin (pIC50 5.6) [1098], GIV3727 (pIC50 5.1–5.2) [1986]
Nomenclature TAS2R41 TAS2R42 TAS2R43 TAS2R45 TAS2R46 TAS2R50 TAS2R60
HGNC, UniProt TAS2R41, P59536 TAS2R42, Q7RTR8 TAS2R43, P59537 TAS2R45, P59539 TAS2R46, P59540 TAS2R50, P59544 TAS2R60, P59551

Further reading on Taste 2 receptors

Palmer RK. (2019) A Pharmacological Perspective on the Study of Taste. Pharmacol. Rev. 71: 20–48 [PMID:30559245]

Other 7TM proteins

Nomenclature GPR107 GPR137 TPRA1 GPR143 GPR157
HGNC, UniProt GPR107, Q5VW38 GPR137, Q96N19 TPRA1, Q86W33 GPR143, P51810 GPR157, Q5UAW9
Endogenous agonists levodopa [1316]
Comments GPR107 is a member of the LUSTR family of proteins found in both plants and animals, having similar topology to G protein-coupled receptors [540] TPRA1 shows no homology to known G protein-coupled receptors. Loss-of-function mutations underlie ocular albinism type 1 [117]. GPR157 has ambiguous sequence similarities to several different GPCR families (class A, class B and the slime mould cyclic AMP receptor). Because of its distant relationship to other GPCRs, it cannot be readily classified.

Further reading on Orphan and other 7TM receptors

Davenport AP et al. (2013) International Union of Basic and Clinical Pharmacology. LXXXVIII. G protein-coupled receptor list: recommendations for new pairings with cognate ligands. Pharmacol. Rev. 65: 967–86 [PMID:23686350]

Gilissen J et al. (2016) Insight into SUCNR1 (GPR91) structure and function. Pharmacol. Ther. 159: 56–65 [PMID:26808164]

Insel PA et al. (2015) G Protein-Coupled Receptor (GPCR) Expression in Native Cells: “Novel” endoGPCRs as Physiologic Regulators and Therapeutic Targets. Mol. Pharmacol. 88: 181-7 [PMID:25737495]

Khan MZ et al. (2017) Neuro-psychopharmacological perspective of Orphan receptors of Rhodopsin (class A) family of G protein-coupled receptors. Psychopharmacology (Berl.) 234: 1181-1207 [PMID:28289782]

Mackenzie AE et al. (2017) The emerging pharmacology and function of GPR35 in the nervous system. Neuropharmacology 113: 661–671 [PMID:26232640]

Ngo T et al. (2016) Identifying ligands at orphan GPCRs: current status using structure-based approaches. Br. J. Pharmacol. 173: 2934-51 [PMID:26837045]

5-Hydroxytryptamine receptors

Overview

5-HT receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on 5-HT receptors [914] and subsequently revised [816]) are, with the exception of the ionotropic 5-HT3 class, GPCRs where the endogenous agonist is 5-hydroxytryptamine. The diversity of metabotropic 5-HT receptors is increased by alternative splicing that produces isoforms of the 5-HT2A (non-functional), 5-HT2C (non-functional), 5-HT4, 5-HT6 (non-functional) and 5-HT7 receptors. Unique amongst the GPCRs, RNA editing produces 5-HT2C receptor isoforms that differ in function, such as efficiency and specificity of coupling to Gq/11 and also pharmacology [181, 2291]. Most 5-HT receptors (except 5-ht1e and 5-ht5b) play specific roles mediating functional responses in different tissues (reviewed by [1765, 2219]).

Nomenclature 5-HT1A receptor 5-HT1B receptor
HGNC, UniProt HTR1A, P08908 HTR1B, P28222
Agonists U92016A [1416], vilazodone (Partial agonist) [463], vortioxetine (Partial agonist) [105] L-694,247 [738], naratriptan (Partial agonist) [1548], eletriptan[1548], frovatriptan [2359], zolmitriptan (Partial agonist) [1548], vortioxetine (Partial agonist) [105], rizatriptan (Partial agonist) [1548]
Selective agonists 8-OH-DPAT [473, 791, 1032, 1251, 1452, 1575, 1577, 1578], NLX-101 [1576] CP94253 [1122]
Antagonists (S)-UH 301 (pKi 7.9) [1575]
Selective antagonists WAY-100635 (pKi 7.9–9.2) [1575, 1577], robalzotan (pKi 9.2) [1007] SB 224289 (Inverse agonist) (pKi 8.2–8.6) [670, 1573, 1924], SB236057 (Inverse agonist) (pKi 8.2) [1445], GR-55562 (pKB 7.4) [915]
Labelled ligands [3H]robalzotan (Antagonist) (pKd 9.8) [994], [3H]WAY100635 (Antagonist) (pKd 9.5) [1075], [3H]8-OH-DPAT (Agonist) [174, 1032, 1574, 1577], [3H]NLX-112 (Agonist) [864], [[11C]WAY100635 (Antagonist) [2161], p-18F]MPPF (Antagonist) [418] [3H]N-methyl-AZ10419369 (Agonist, Partial agonist) [1356], [3H]GR 125,743 (Selective Antagonist) (pKd 8.6–9.2) [738, 2350], [3H]alniditan (Agonist) [1260], [125I]GTI (Agonist) [213, 256] – Rat, [3H]eletriptan (Agonist, Partial agonist) [1548], [3H]sumatriptan (Agonist, Partial agonist) [1548], [11C]AZ10419369 (Agonist, Partial agonist) [2207]
Nomenclature 5-HT1D receptor 5-ht1e receptor 5-HT1F receptor
HGNC, UniProt HTR1D, P28221 HTR1E, P28566 HTR1F, P30939
Agonists dihydroergotamine [790, 1260, 1267], ergotamine [711], L-694,247 [2340], naratriptan [506, 1548, 1794], zolmitriptan[1548], frovatriptan [2359], rizatriptan[1548] BRL-54443 [250] BRL-54443 [250], eletriptan [1548], sumatriptan [12, 13, 1548, 2236]
Selective agonists PNU109291 [564] – Gorilla, eletriptan [1548] lasmiditan [1563], LY334370 [2236], 5-BODMT [1113], LY344864 [1702]
Selective antagonists SB 714786 (pKi 9.1) [2264]
Labelled ligands [3H]eletriptan (Agonist) [1548], [3H]alniditan (Agonist) [1260], [125I]GTI (Selective Agonist) [213, 256] – Rat, [3H]GR 125,743 (Selective Antagonist) (pKd 8.6) [2350], [3H]sumatriptan (Agonist) [1548] [3H]5-HT (Agonist) [1413, 1657] [3H]LY334370 (Agonist) [2236], [125I]LSD (Agonist) [48] – Mouse
Nomenclature 5-HT2A receptor 5-HT2B receptor 5-HT2C receptor
HGNC, UniProt HTR2A, P28223 HTR2B, P41595 HTR2C, P28335
Agonists DOI [227, 1562, 1986] methysergide (Partial agonist) [1117, 1827, 2237], DOI [1179, 1562, 1883] DOI [544, 1562, 1883], Ro 60-0175 [1097, 1117]
Selective agonists BW723C86 [124, 1117, 1883], Ro 60-0175[1117] WAY-163909 [533], lorcaserin [2125]
Antagonists risperidone (Inverse agonist) (pKi 9.3–10) [1131, 1156, 1901], mianserin (pKi 7.7–9.6) [1117, 1146, 1452], ziprasidone (pKi 8.8–9.5) [1131, 1156, 1901, 1939], volinanserin (pIC50 6.5–9.3) [1117, 1317, 1782], blonanserin (pKi 9.1) [1611], clozapine (Inverse agonist) (pKi 7.6–9) [1117, 1156, 1449, 1901, 2201], H05 (pIC50 7.2) [2356] mianserin (pKi 7.9–8.8) [200, 1117, 2237] mianserin (Inverse agonist) (pKi 8.3–9.2) [607, 1117, 1452], methysergide (pKi 8.6–9.1) [544, 1117], ziprasidone (Inverse agonist) (pKi 7.9–9) [858, 1156, 1939], olanzapine (Inverse agonist) (pKi 8.1–8.4) [858, 1156, 1939], loxapine (Inverse agonist) (pKi 7.8–8) [858, 1156]
Selective antagonists compound 3b (pKi 10.6) [603], ketanserin (pKi 8.1–9.7) [261, 1117, 1771], pimavanserin (Inverse agonist) (pKi 9.3) [659, 2201] BF-1 (pKi 10.1) [1895], RS-127445 (pKi 9–9.5) [200, 1117], EGIS-7625 (pKi 9) [1146] FR260010 (pKi 9) [807], SB 242084 (pKi 8.2–9) [1071, 1117], RS-102221 (pKi 8.3–8.4) [201, 1117]
Labelled ligands [3H]fananserin (Antagonist) (pKd 9.9) [1362] – Rat, [3H]ketanserin (Antagonist) (pKd 8.6–9.7) [1117, 1771], [11C]volinanserin (Antagonist) [784], [18F]altanserin (Antagonist) [1823] [3H]LSD (Agonist) [1771], [3H]5-HT (Agonist) [2235] – Rat, [3H]mesulergine (Antagonist, Inverse agonist) (pKd 7.9) [1117], [125I]DOI (Agonist) [3H]mesulergine (Antagonist, Inverse agonist) (pKd 8.7–9.3) [607, 1771], [125I]DOI (Agonist) [607], [3H]LSD (Agonist)
Nomenclature 5-HT4 receptor 5-HT5A receptor 5-ht5b receptor
HGNC, UniProt HTR4, Q13639 HTR5A, P47898 HTR5BP, –
Agonists cisapride (Partial agonist) [89, 141, 690, 1442, 1443, 2192]
Selective agonists TD-8954 [1427], ML 10302 (Partial agonist) [152, 178, 1440, 1441, 1442], RS67506 [842] – Rat, relenopride (Partial agonist) [702], velusetrag [1314, 1994], BIMU 8 [398]
Selective antagonists RS 100235 (pKi 8.7–12.2) [398, 1809], SB 204070 (pKi 9.8–10.4) [141, 1442, 1441, 2192], GR 113808 (pKi 9.3–10.3) [89, 141, 178, 398, 1443, 1809, 2190] SB 699551 (pKi 8.2) [416]
Labelled ligands [3H]GR 113808 (Antagonist) (pKd 9.7–10.3) [89, 141, 1442, 2190], [123I]SB 207710 (Antagonist) (pKd 10.1) [251] – Pig, [3H]RS 57639 (Selective Antagonist) (pKd 9.7) [199] – Guinea pig, [11C]SB207145 (Antagonist) (pKd 8.6) [1344] [125I]LSD (Agonist) [737], [3H]5-CT (Agonist) [737] [125I]LSD (Agonist) [1404] – Mouse, [3H]5-CT (Agonist) [2233] – Mouse
Nomenclature 5-HT6 receptor 5-HT7 receptor
HGNC, UniProt HTR6, P50406 HTR7, P34969
Selective agonists WAY-181187 [1887], E6801 (Partial agonist) [893], WAY-208466 [151], EMD-386088 [1405] LP-12 [1257], LP-44 [1257], LP-211 [1258] – Rat, AS-19 [1091], E55888 [229]
Antagonists lurasidone (pKi 9.3) [954], pimozide (pKi 9.3) [1826] – Rat, vortioxetine (pKi 6.3) [105]
Selective antagonists SB399885 (pKi 9) [882], SB 271046 (pKi 8.9) [247], cerlapirdine (pKi 8.9) [407], SB357134 (pKi 8.5) [248], Ro 63-0563 (pKi 7.9–8.4) [184, 1985] SB269970 (pKi 8.6–8.9) [2119], SB656104 (pKi 8.7) [613], DR-4004 (pKi 8.7) [710, 1082], JNJ-18038683 (pKi 8.2) [197], SB 258719 (Inverse agonist) (pKi 7.5) [2120]
Labelled ligands [11C]GSK215083 (Antagonist) (pKi 9.8) [1656], [125I]SB258585 (Selective Antagonist) (pKd 9) [882], [3H]LSD (Agonist) [183], [3H]Ro 63-0563 (Antagonist) (pKd 8.3) [184], [3H]5-CT (Agonist) [3H]5-CT (Agonist) [2119], [3H]5-HT (Agonist) [107, 2026], [3H]SB269970 (Selective Antagonist) (pKd 8.9) [2119], [3H]LSD (Agonist) [2026]

Comments

Tabulated pKi and KD values refer to binding to human 5-HT receptors unless indicated otherwise. The nomenclature of 5-HT1B/5-HT1D receptors has been revised [816]. Only the non-rodent form of the receptor was previously called 5-HT1D: the human 5-HT1B receptor (tabulated) displays a different pharmacology to the rodent forms of the receptor due to Thr335 of the human sequence being replaced by Asn in rodent receptors [800]. Wang et al. (2013) report X-ray structures which reveal the binding modality of ergotamine and dihydroergotamine (DHE) to the 5-HT1B receptor in comparison with the structure of the 5HT2B receptor [2249]; some of these drugs adopt rather different conformations depending on the target receptor [1681]. Various 5-HT receptors have multiple partners in addition to G proteins, which may affect function and pharmacology [1384]. NAS181 is a selective antagonist of the rodent 5-HT1B receptor. Fananserin (LSD) and ketanserin bind with high affinity to dopamine D4 and histamine H1 receptors respectively, and ketanserin is a potent α1 adrenoceptor antagonist, in addition to blocking 5-HT2A receptors. Lysergic acid (LSD) and ergotamine show a strong preference for arrestin recruitment over G protein coupling at the 5-HT2B receptor, with no such preference evident at 5-HT1B receptors, and they also antagonise 5-HT7A receptors [2231]. DHE (dihydroergocryptine), pergolide and cabergoline also show significant preference for arrestin recruitment over G protein coupling at 5-HT2B receptors [2231]. The 5-HT2B (and other 5-HT) receptors interact with immunocompetent cells [1645]. The serotonin antagonist mesulergine was key to the discovery of the 5HT2C receptor [1672], initially known as 5-HT1C [83]. The human 5-HT5A receptor may couple to several signal transduction pathways when stably expressed in C6 glioma cells [1599] and rodent prefrontal cortex (layer V pyramidal neurons) [724]. The human orthologue of the mouse 5-ht5b receptor is non-functional (stop codons); the 5-ht1e receptor has not been cloned from mouse, or rat, impeding definition of its function [800]. In addition to accepted receptors, an ’orphan’ receptor, unofficially termed5-HT1P, has been described [695].

Further reading on 5-Hydroxytryptamine receptors

Bockaert J et al. (2011) 5-HT(4) receptors, a place in the sun: act two. Curr Opin Pharmacol 11: 87-93 [PMID:21342787]

Hayes DJ et al. (2011) 5-HT receptors and reward-related behaviour: a review. Neurosci Biobehav Rev 35: 1419-49 [PMID:21402098]

Hoyer D et al. (1994) International Union of Pharmacology classification of receptors for 5hydroxytryptamine (Serotonin). Pharmacol. Rev. 46: 157-203 [PMID:7938165]

Leopoldo M et al. (2011)Serotonin 5-HT7 receptor agents: Structure-activity relationships and potential therapeutic applications in central nervous system disorders. Pharmacol. Ther. 129: 120-48 [PMID:20923682]

Meltzer HY et al. (2011) The role of serotonin receptors in the action of atypical antipsychotic drugs. Curr Opin Pharmacol 11: 59-67 [PMID:21420906]

Roberts AJ et al. (2012) The 5-HT(7) receptor in learning and memory. Hippocampus 22: 762-71 [PMID:21484935]

Acetylcholine receptors (muscarinic)

Overview

Muscarinic acetylcholine receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on Muscarinic Acetylcholine Receptors [318]) are GPCRs of the Class A, rhodopsin-like family where the endogenous agonist is acetylcholine. In addition to the agents listed in the table, AC-42, its structural analogues AC-260584 and 77-LH-28-1, N-desmethylclozapine, TBPB and LuAE51090 have been described as functionally selective agonists of the M1 receptor subtype via binding in a mode distinct from that utilized by non-selective agonists [82, 1014, 1198, 1199, 1408, 1859, 2018, 2019, 2061]. There are two pharmacologically characterised allosteric sites on muscarinic receptors, one defined by it binding gallamine, strychnine and brucine, and the other defined by the binding of KT 5720, WIN 62,577, WIN 51,708 and staurosporine [1215, 1216].

Nomenclature M1 receptor M2 receptor
HGNC, UniProt CHRM1, P11229 CHRM2, P08172
Agonists carbachol [385, 976, 2326], pilocarpine (Partial agonist) [976], bethanechol[976] carbachol [358, 976, 1147], bethanechol[976]
Selective agonists SPP1 [242]
Antagonists glycopyrrolate (pIC50 9.9) [2037], AE9C90CB (pKi 9.7) [1979], atropine (pKi 8.5–9.6) [385, 636, 878, 923, 1683, 1993], tiotropium (pKi 9.6) [501], 4-DAMP (pKi 9.2) [537] tiotropium (pKi 9.9) [501], glycopyrrolate (pIC50 9.3) [2037], atropine (pKi 7.8–9.2) [265, 358, 878, 923, 1147, 1561, 1683], AE9C90CB (pKi 8.6) [1979], tolterodine (Inverse agonist) (pKi 8.4–8.6) [704, 1561, 1979]
Selective antagonists biperiden (pKd 9.3) [190], VU0255035 (pKi 7.8) [1943], guanylpirenzepine (pKi 7.3–7.6) [25, 2234] – Rat tripitramine (pKi 9.6) [1351]
Allosteric modulators muscarinic toxin 7 (Negative) (pKi 11–11.1) [1606], benzoquinazolinone 12 (Positive) (pKB 6.6) [4], KT 5720 (Positive) (pKd 6.4) [1215], brucine (Positive) (pKd 4.5–5.8) [976, 1214], BQCA (Positive) (pKB 4–4.8) [4, 5, 296, 1336], VU0029767 (Positive) [1385], VU0090157 (Positive) [1385] W-84 (Negative) (pKd 6–7.5) [1470, 2155], C7/3-phth (Negative) (pKd 7.1) [386], alcuronium (Negative) (pKd 6.1–6.9) [976, 2155], gallamine (Negative) (pKd 5.9–6.3) [399, 1212], LY2119620 (Positive) (pKd 5.7) [437, 1158], LY2033298 (Positive) (pKd 4.4) [2185]
Labelled ligands [3H]QNB (Antagonist) (pKd 10.6–10.8) [387, 1683], Cy3B-telenzepine (Antagonist) (pKd 10.5) [856], [3H]N-methyl scopolamine (Antagonist) (pKd 9.4–10.3) [324, 385, 387, 878, 976, 977, 1011, 1074, 1212], [3H](+)telenzepine (Antagonist) (pKi 9.4) [580] – Rat, Alexa-488-telenzepine (Antagonist) (pKd 9.3) [856], [3H]pirenzepine (Antagonist) (pKd 7.9) [2273] [3H]QNB (Antagonist) (pKd 10.1–10.6) [1683], Cy3B-telenzepine (Antagonist) (pKi 10.4) [1568], [3H]tiotropium (Antagonist) (pKd 10.3) [1856], [3H]N-methyl scopolamine (Antagonist) (pKd 9.3–9.9) [324, 358, 878, 976, 977, 1011, 1074, 1212, 2261], Alexa-488-telenzepine (Antagonist) (pKi 8.8) [1568], [3H]acetylcholine (Agonist) [1213], [3H]oxotremorine-M (Agonist) [153], [3H]dimethyl-W84 (Allosteric modulator, Positive) (pKd 8.5) [2154], [18F]FP-TZTP (Agonist) [975] – Mouse
Nomenclature M3 receptor M4 receptor M5 receptor
HGNC, UniProt CHRM3, P20309 CHRM4, P08173 CHRM5, P08912
Agonists pilocarpine (Partial agonist) [976], carbachol [358, 976, 2326], bethanechol [976] pilocarpine (Partial agonist) [976], carbachol[976, 2326], bethanechol[976] pilocarpine (Partial agonist) [740], carbachol [2326]
Antagonists tiotropium (pKi 9.5–11.1) [501, 519], AE9C90CB (pKi 9.9) [1979], atropine (pKi 8.9–9.8) [265, 519, 878, 923, 1683, 1993], ipratropium (pKi 9.3–9.8) [519, 878], aclidinium (pIC50 9.8) [1733] glycopyrrolate (pIC50 9.8) [2037], AE9C90CB (pKi 9.5) [1979], 4-DAMP (pKi 8.9) [537], oxybutynin (pKi 8.7) [1979], biperiden (pKd 8.6) [190], UH-AH 37 (pKi 8.3–8.4) [704, 2292] glycopyrrolate (pIC50 9.7) [2037], AE9C90CB (pKi 9.5) [1979], 4-DAMP (pKi 9) [537], tolterodine (pKi 8.5–8.8) [704, 1979], darifenacin (pKi 7.9–8.6) [704, 841, 878, 1979]
Selective antagonists ML381 (pKi 6.3) [684]
Allosteric modulators WIN 62,577 (Positive) (pKd 5.1) [1216], N-chloromethyl-brucine (Positive) (pKd 3.3) [1214] muscarinic toxin 3 (Negative) (pKi 8.7) [1011, 1635], VU0152100 (Positive) (pEC50 6.4) [224] – Rat, VU0152099 (Positive) (pEC50 6.4) [224] – Rat, LY2119620 (Positive) (pKd 5.7) [437], thiochrome (Positive) (pKd 4) [1213], LY2033298 (Positive) [333] ML380 (Positive) (pEC50 6.7) [149, 686]
Selective allosteric modulators ML375 (Negative) (pIC50 6.5) [685]
Labelled ligands [3H]tiotropium (Antagonist) (pKd 10.7) [1856], [3H]QNB (Antagonist) (pKd 10.4) [1683], [3H]N-methyl scopolamine (Antagonist) (pKd 9.7–10.2) [324, 358, 878, 923, 976, 1011, 1074, 1212], [3H]darifenacin (Antagonist) (pKd 9.5) [1993] [3H]QNB (Antagonist) (pKd 9.7–10.5) [387, 1683], [3H]N-methyl scopolamine (Antagonist) (pKd 9.9–10.2) [324, 358, 387, 878, 976, 1011, 1074, 1212, 1635, 2261], [3H]acetylcholine (Agonist) [1213] [3H]QNB (Antagonist) (pKd 10.2–10.7), [3H]N-methyl scopolamine (Antagonist) (pKd 9.3–9.7) [324, 358, 878, 1011, 1074, 2261]

Comments

The crystal structures of the M1-M4 receptor subtypes have been reported [777, 2111, 2382]. Direct activation via an allosteric site has been reported for M1 receptors (BQCA, PF-06767832) and M4 receptors (LY2033298) [462, 1225, 1227, 1336, 1550, 1551]. The allosteric site for gallamine and strychnine on M2 receptors can be labelled by [3H]dimethyl-W84 [2155]. McN-A-343 is a functionally selective partial agonist that appears to interact in a bitopic mode with both the orthosteric and an allosteric site on the M2 muscarinic receptor [2186]. THRX160209, hybrid 1 and hybrid 2, are multivalent (bitopic) ligands that also achieve selectivity for M2 receptors by binding both to the orthosteric and a nearby allosteric site [59, 2028].

Although numerous ligands for muscarinic acetylcholine receptors have been described, relatively few selective antagonists have been described, so it is common to assess the rank order of affinity of a number of antagonists of limited selectivity (e.g. 4-DAMP, darifenacin, pirenzepine) in order to identify the involvement of particular subtypes. It should be noted that the measured affinities of antagonists (and agonists) in radioligand binding studies are sensitive to ionic strength and can increase over 10-fold at low ionic strength compared to their values at physiological ionic strengths [167].

Further reading on Acetylcholine receptors (muscarinic)

Burger WAC et al. (2018) Toward an understanding of the structural basis of allostery in muscarinic acetylcholine receptors. J Gen Physiol 150: 1360-1372 [PMID:30190312]

Caulfield MP et al. (1998) International Union of Pharmacology. XVII. Classification of muscarinic acetylcholine receptors. Pharmacol Rev 50: 279-290 [PMID:9647869]

Eglen RM. (2012) Overview of muscarinic receptor subtypes. Handb Exp Pharmacol 3-28 [PMID:22222692]

Kruse AC et al. (2014) Muscarinic acetylcholine receptors: novel opportunities for drug development. Nat Rev Drug Discov 13: 549-60 [PMID:24903776]

Leach K et al. (2012) Structure-function studies of muscarinic acetylcholine receptors. Handb Exp Pharmacol 29-48 [PMID:22222693]

Valant C et al. (2012) The best of both worlds? Bitopic orthosteric/allosteric ligands of g proteincoupled receptors. Annu Rev Pharmacol Toxicol 52: 153-78 [PMID:21910627]

Adenosine receptors

Overview

Adenosine receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on Adenosine Receptors [624]) are activated by the endogenous ligand adenosine (potentially inosine also at A3 receptors). Crystal structures for the antagonist-bound [410, 964, 1307, 1922], agonist-bound [1232, 1233, 2354] and G protein-bound A2A adenosine receptors [307] have been described. The structures of an antagonist-bound A1 receptor [712] and an adenosine-bound A1 receptor-Gi complex [521] have been resolved by cryo-electronmicroscopy. Another structure of an antagonist-bound A1 receptor obtained with X-ray crystallography has also been reported [361].

Nomenclature A1 receptor A2A receptor A2B receptor A3 receptor
HGNC, UniProt ADORA1, P30542 ADORA2A, P29274 ADORA2B, P29275 ADORA3, P0DMS8
Endogenous agonists adenosine [2369] adenosine [2369] adenosine [2369] adenosine [2369]
Agonists NECA [658, 1005, 1813, 2151, 2369] NECA [209, 500, 658, 1088, 1173, 2369] NECA [160, 209, 995, 1289, 2033, 2203, 2369] NECA [209, 658, 971, 1858, 2204, 2369]
Selective agonists cyclopentyladenosine [442, 469, 658, 848, 968, 1005, 1813], 5-Cl-5-deoxy-(±)-ENBA [620], TCPA [162], CCPA[968, 1609], MRS7469 [2148] apadenoson [1674], UK-432,097 [768, 2354], AZD4635 [410], CGS 21680 [209, 500, 658, 968, 1088, 1115, 1173, 1609], regadenoson[968] BAY 60-6583 [539] piclidenoson [592, 647, 1115, 2204], Cl-IB-MECA [225, 971, 1085], MRS5698 [2147]
Antagonists CGS 15943 (pKi 8.5) [1636], xanthine amine congener (pKd 7.5) [620] CGS 15943 (pKi 7.7–9.4) [500, 1088, 1115, 1636], xanthine amine congener (pKi 8.4–9) [500, 1115] xanthine amine congener (pKi 6.9–8.8) [160, 995, 996, 1115, 1289, 2033], CGS 15943 (pKi 6–8.1) [76, 995, 996, 1115, 1636, 2033] CGS 15943 (pKi 7–7.9) [1093, 1115, 1636, 2204], xanthine amine congener (pKi 7–7.4) [1115, 1858, 2204]
Selective antagonists PSB36 (pKi 9.9) [6] – Rat, DPCPX (pKi 7.4–9.2) [469, 950, 1609, 1813, 2295], derenofylline (pKi 9) [1033], WRC-0571 (pKi 8.8) [1387], DU172 (pKi 7.4) [712] SCH442416 (pKi 8.4–10.3) [1957, 2139], ZM-241385 (pKi 8.8–9.1) [1636] PSB-0788 (pKi 9.4) [208], PSB603 (pKi 9.3) [208], MRS1754 (pKi 8.8) [995, 1092], PSB1115 (pKi 7.3) [832] MRS1220 (pKi 8.2–9.2) [971, 1093, 2055, 2384], VUF5574 (pKi 8.4) [2193], MRS1523 (pKi 7.7) [1268], MRS1191 (pKi 7.5) [971, 998, 1273]
Allosteric modulators PD81723 (Positive) [258] LUF6000 (Positive) [772], LUF6096 (Positive) [847]
Labelled ligands [3H]CCPA (Agonist) [1115, 1813], [3H]DPCPX (Antagonist) (pKd 8.4–9.2) [442, 592, 1115, 1636, 1813, 2151] [3H]ZM 241385 (Antagonist) (pKd 8.7–9.1) [39, 656], [3H]CGS 21680 (Agonist) [983, 2246] [3H]MRS1754 (Antagonist) (pKd 9.8) [995] [125I]AB-MECA (Agonist) [1636, 2204]

Comments

Adenosine inhibits many intracellular ATP-utilising enzymes, including adenylyl cyclase (P-site). A pseudogene exists for the A2B adenosine receptor (ADORA2BP1) with 79% identity to the A2B adenosine receptor cDNA coding sequence, but which is unable to encode a functional receptor [972]. DPCPX also exhibits antagonism at A2B receptors (pKi ca. 7,[37, 1115]). Antagonists at A3 receptors exhibit marked species differences, such that only MRS1523 and MRS1191 are selective at the rat A3 receptor. In the absence of other adenosine receptors, [3H]DPCPX and [3H]ZM 241385 can also be used to label A2B receptors (KD ca. 30 and 60 nM respectively). [125I]AB-MECA also binds to A1 receptors [1115]. [3H]CGS 21680 is relatively selective for A2A receptors, but may also bind to other sites in cerebral cortex [438, 1006]. [3H]NECA binds to other non-receptor elements, which also recognise adenosine [1318]. XAC-BY630 has been described as a fluorescent antagonist for labelling A1 adenosine receptors in living cells, although activity at other adenosine receptors was not examined [234].

Further reading on Adenosine receptors

Borea PA et al. (2015) The A3 adenosine receptor: history and perspectives. Pharmacol Rev 67: 74-102 [PMID:25387804]

Cronstein BN et al. (2017) Adenosine and adenosine receptors in the pathogenesis and treatment of rheumatic diseases. Nat Rev Rheumatol 13: 41-51 [PMID:27829671]

Fredholm BB et al. (2011) International Union of Basic and Clinical Pharmacology. LXXXI. Nomenclature and classification of adenosine receptors–an update. Pharmacol Rev 63: 1-34 [PMID:21303899]

Guo D et al. (2017) Kinetic Aspects of the Interaction between Ligand and G Protein-Coupled Receptor: The Case of the Adenosine Receptors. Chem Rev 117: 38-66 [PMID:27088232]

Göblyös A et al. (2011) Allosteric modulation of adenosine receptors. Biochim Biophys Acta 1808: 1309-18 [PMID:20599682]

Lasley RD. (2011) Adenosine receptors and membrane microdomains. Biochim Biophys Acta 1808: 1284-9 [PMID:20888790]

Mundell S et al. (2011) Adenosine receptor desensitization and trafficking. Biochim Biophys Acta 1808: 1319-28 [PMID:20550943]

Vecchio EA et al. (2018) New paradigms in adenosine receptor pharmacology: allostery, oligomerization and biased agonism. Br J Pharmacol 175: 4036-4046 [PMID:29679502]

Wei CJ etal. (2011)Normaland abnormalfunctions ofadenosine receptors inthecentral nervous system revealed by genetic knockout studies. Biochim Biophys Acta 1808: 1358-79[PMID:21185258]

Adhesion Class GPCRs

Overview

Adhesion GPCRs are structurally identified on the basis of a large extracellular region, similar to the Class B GPCR, but which is linked to the 7TM region by a GPCR autoproteolysisinducing (GAIN) domain [60] containing a GPCR proteolytic site. The N-terminus often shares structural homology with adhesive domains (e.g. cadherins, immunolobulin, lectins) facilitating inter- and matricellular interactions and leading to the term adhesion GPCR [626, 2397]. Several receptors have been suggested to function as mechanosensors [219, 1697, 1900, 2310]. The nomenclature of these receptors was revised in 2015 as recommended by NC-IUPHAR and the Adhesion GPCR Consortium [788].

Nomenclature ADGRA1 ADGRA2 ADGRA3 ADGRB1 ADGRB2 ADGRB3
HGNC, UniProt ADGRA1, Q86SQ6 ADGRA2, Q96PE1 ADGRA3, Q8IWK6 ADGRB1, O14514 ADGRB2, O60241 ADGRB3, O60242
Endogenous agonists phosphatidylserine [1655]
Comments Required to assemble higher-order Reck/Gpr124/Frizzled/ Lrp5/6 complexes [573, 1726, 2188, 2200, 2436]. Reported to mediate phagocytosis through binding of phosphatidylserine [1655] and lipopolysaccharide [447]. Reported to bind C1q-like molecules [194].
Nomenclature CELSR1 CELSR2 CELSR3 ADGRD1 ADGRD2
HGNC, UniProt CELSR1, Q9NYQ6 CELSR2, Q9HCU4 CELSR3, Q9NYQ7 ADGRD1, Q6QNK2 ADGRD2, Q7Z7M1
Comments Mutated in Joubert syndrome patients [2218]. High-confidence risk gene for Tourette syndrome [2260]. Is a Gs protein-coupled receptor [186, 1278] and highly expressed in glioblastoma [122].
Nomenclature ADGRE1 ADGRE2 ADGRE3 ADGRE4P ADGRE5
HGNC, UniProt ADGRE1, Q14246 ADGRE2, Q9UHX3 ADGRE3, Q9BY15 ADGRE4P, Q86SQ3 ADGRE5, P48960
Comments A mutation destabilizing the GAIN domain sensitizes mast cells to IgE-independent vibration-induced degranulation [219]. Reported to bind chondroitin sulfate B [2024]. Reported to bind CD55 [789], chondroitin sulfate B [2024], α5β1 and αγβ3 integrins [2262], and CD90 [2248].
Nomenclature ADGRF1 ADGRF2 ADGRF3 ADGRF4 ADGRF5
HGNC, UniProt ADGRF1, Q5T601 ADGRF2, Q8IZF7 ADGRF3, Q8IZF5 ADGRF4, Q8IZF3 ADGRF5, Q8IZF2
Comments Synaptamide is an agonist at ADGRF1 supporting neurogenesis [1240] and couples to Gs and Gq pathways [482, 2041]. ADGRF2 is highly expressed in squamous epithelia and gene deficiency did not result in detectable defects [1744]. ADGRF3 is highly expressed in gastrointestinal neuroendocrine tumors [308, 308]. ADGRF4 couples to Gq/11 proteins [482], is highly expressed in squamous epithelia and gene deficiency did not result in detectable defects [1744]. ADGRF5 controls alveolar surfactant secretion via Gq/11 pathway [253].
Nomenclature ADGRG1 ADGRG2 ADGRG3 ADGRG4 ADGRG5 ADGRG6 ADGRG7
HGNC, UniProt ADGRG1, Q9Y653 ADGRG2, Q8IZP9 ADGRG3, Q86Y34 ADGRG4, Q8IZF6 ADGRG5, Q8IZF4 ADGRG6, Q86SQ4 ADGRG7, Q96K78
Comments Reported to bind tissue transglutaminase 2 [2355] and collagen, which activates the G12/13 pathway [1330]. ADGRG2 is coupled to Gq and Gs pathways [481] and gene deficiency causes congenital obstructive azoospermia [1663]. ADGRG3 is expressed in immune cells [1947, 2255] and couples to Go proteins [770]. ADGRG4 is highly expressed in enterochromaffin cells and gastrointestinal neuroendocrine tumors [1250]. ADGRG5 is a constitutively active Gs protein-coupled receptor [770, 2310], highly expressed in eosinophils and NK cells [1682]. ADGRG6 is a key regulator of Schwann cell-mediated myelination [1481], and couples to Gs and Gi/o pathways [1468]. ADGRG7 is expressed in interstine and involved in interstine contractility regulation [1580].
Nomenclature ADGRL1 ADGRL2 ADGRL3 ADGRL4 ADGRV1
HGNC, UniProt ADGRL1, O94910 ADGRL2, O95490 ADGRL3, Q9HAR2 ADGRL4, Q9HBW9 ADGRV1, Q8WXG9
Comments Couples to Gs and Gq pathways [1252, 1533]. A LPHN3 gene variant in humans is associated with attention-deficit-hyperactivity disorder [62, 2313]. Loss-of-function mutations are associated with Usher syndrome, a sensory deficit disorder [973].

Further reading on Adhesion Class GPCRs

Hamann J et al. (2015) International Union of Basic and Clinical Pharmacology. XCIV. Adhesion G protein-coupled receptors. Pharmacol Rev 67: 338-67 [PMID:25713288]

Langenhan T et al. (2013) Sticky signaling–adhesion class G protein-coupled receptors take the stage. Sci Signal 6: re3 [PMID:23695165]

Liebscher I et al. (2016) Tethered Agonism: A Common Activation Mechanism of Adhesion GPCRs. Handb Exp Pharmacol 234: 111-125 [PMID:27832486]

Monk KR et al. (2015) Adhesion G Protein-Coupled Receptors: From In Vitro Pharmacology to In Vivo Mechanisms. Mol Pharmacol 88: 617-23 [PMID:25956432]

Purcell RH et al. (2018) Adhesion G Protein-Coupled Receptors as Drug Targets. Annu Rev Pharmacol Toxicol 58: 429-449 [PMID:28968187]

Adrenoceptors

Overview

The nomenclature of the Adrenoceptors has been agreed by the NC-IUPHAR Subcommittee on Adrenoceptors [277], see also [869].

Adrenoceptors, α1

α1-Adrenoceptors are activated by the endogenous agonists (-)-adrenaline and (-)-noradrenaline. Phenylephrine, methoxamine and cirazoline are agonists and prazosin and cirazoline antagonists considered selective for α1- relative to α2-adrenoceptors. [3H]prazosin and [125I]HEAT (BE2254) are relatively selective radioligands. S(+)-niguldipine also has high affinity for L-type Ca2+ channels. Fluorescent derivatives of prazosin (Bodipy PLprazosin- QAPB) are used to examine cellular localisation of α1-adrenoceptors. Selective α1-adrenoceptor agonists are used as nasal decongestants; antagonists to treat hypertension (doxazosin, prazosin) and benign prostatic hyperplasia (alfuzosin, tamsulosin). The α1- and β2-adrenoceptor antagonist carvedilol is used to treat congestive heart failure, although the contribution of α1-adrenoceptor blockade to the therapeutic effect is unclear. Several anti-depressants and anti-psychotic drugs are α1-adrenoceptor antagonists contributing to side effects such as orthostatic hypotension and extrapyramidal effects.

Nomenclature α1A-adrenoceptor α1B-adrenoceptor α1D-adrenoceptor
HGNC, UniProt ADRA1A, P35348 ADRA1B, P35368 ADRA1D, P25100
Endogenous agonists (-)-adrenaline [904, 1948], (-)-noradrenaline [904, 1948, 2104] (-)-noradrenaline [904, 1948], (-)-adrenaline [904, 1948]
Agonists oxymetazoline [904, 1610, 1948, 2104], phenylephrine [2104], methoxamine[1948, 2104] phenylephrine [614, 1459]
Selective agonists A61603 [614, 1116], dabuzalgron [179]
Antagonists prazosin (Inverse agonist) (pKi 9–9.9) [335, 443, 614, 1948, 2312], doxazosin (pKi 9.3) [795], terazosin (pKi 8.7) [1436], phentolamine (pKi 8.6) [1948], alfuzosin (pKi 8.1) [867] prazosin (Inverse agonist) (pKi 9.6–9.9) [614, 1948, 2312], tamsulosin (Inverse agonist) (pKi 9.5–9.7) [614, 1948, 2312], doxazosin (pKi 9.1) [795], alfuzosin (pKi 8.6) [868], terazosin (pKi 8.6) [1436], phentolamine (pKi 7.5) [1948] prazosin (Inverse agonist) (pKi 9.5–10.2) [614, 1948, 2312], tamsulosin (pKi 9.8–10.2) [614, 1948, 2312], doxazosin (pKi 9.1) [795], terazosin (pKi 9.1) [1436], alfuzosin (pKi 8.4) [867], dapiprazole (pKi 8.4) [79], phentolamine (Inverse agonist) (pKi 8.2) [1948], RS-100329 (pKi 7.9) [2312], labetalol (pKi 6.6) [79]
Selective antagonists tamsulosin (pKi 10–10.7) [335, 443, 614, 1948, 2312], silodosin (pKi 10.4) [1948], S(+)-niguldipine (pKi 9.1–10) [614, 1948], RS-100329 (pKi 9.6) [2312], SNAP5089 (pKi 8.8–9.4) [867, 1256, 2294], ρ-Da1a (pKi 9.2–9.3) [1412, 1755], RS-17053 (pKi 9.2–9.3) [335, 443, 611, 614] Rec 15/2615 (pKi 9.5) [2110], L-765314 (pKi 7.7) [1662], AH 11110 (pKi 7.5) [1875] BMY-7378 (pKi 8.7–9.1) [310, 2403]

Comments

The α1C-adrenoceptor corresponds to the pharmacologically defined α1A-adrenoceptor [869]. Some tissues possess α1A-adrenoceptors (α1L-adrenoceptors [614, 1501]) that display relatively low affinity in functional and binding assays for prazosin indicative of different receptor states or locations. α1A-adrenoceptor C-terminal splice variants form homo- and heterodimers, but fail to generate a functional α1L-adrenoceptor [1768]. α1D-Adrenoceptors form heterodimers with α1B- or β2-adrenoceptors that show increased cell-surface expression [2164]. Recombinant α1D-adrenoceptors have been shown in some heterologous systems to be mainly located intracellularly but cell-surface localization is encouraged by truncation of the Nterminus, or by co-expression of α1B- or β2-adrenoceptors [779, 2164]. In blood vessels all three α1-adrenoceptor subtypes are located on the surface and intracellularly [1433, 1434]. Signalling is predominantly via Gq/11 butα1-adrenoceptors also couple toGi/o, Gs and G12/13. Several α1A-adrenoceptor agonists display ligand directed signalling bias relative to noradrenaline [575]. There are also differences between subtypes in coupling efficiency to different pathways. In vascular smooth muscle, the potency of agonists is related to the predominant subtype, α1D- conveying greater agonist sensitivity than α1A-adrenoceptors [609].

Adrenoceptors, α2

α2-Adrenoceptors are activated by (-)-adrenaline and with lower potency by (-)-noradrenaline. Brimonidine and talipexole are agonists and rauwolscine and yohimbine antagonists selective for α2- relative to α1-adrenoceptors. [3H]rauwolscine, [3H]brimonidine and [3H]RX821002 are relatively selective radioligands. There is species variation in the pharmacology of the α2A-adrenoceptor. Multiple mutations of α2-adrenoceptors have been described, some associated with alterations in function. Presynaptic α2-adrenoceptors regulate many functions in the nervous system. The α2-adrenoceptor agonists clonidine, guanabenz and brimonidine affect central baroreflex control (hypotension and bradycardia), induce hypnotic effects and analgesia, and modulate seizure activity and platelet aggregation. Clonidine is an anti-hypertensive and counteracts opioid withdrawal. Dexmedetomidine (also xylazine) is used as a sedative and analgesic in human and veterinary medicine with sympatholytic and anxiolytic properties. The α2-adrenoceptor antagonist yohimbine has been used to treat erectile dysfunction and mirtazapine as an anti-depressant. The α2B subtype appears to be involved in neurotransmission in the spinal cord and α2C in regulating catecholamine release from adrenal chromaffin cells.

Nomenclature α2A-adrenoceptor α2B-adrenoceptor α2C-adrenoceptor
HGNC, UniProt ADRA2A, P08913 ADRA2B, P18089 ADRA2C, P18825
Endogenous agonists (-)-adrenaline [985, 1704], (-)-noradrenaline [985, 1704] (-)-noradrenaline (Partial agonist) [985, 1704], (-)-adrenaline[985] (-)-noradrenaline [985, 1704], (-)-adrenaline [985]
Agonists dexmedetomidine (Partial agonist) [985, 1339, 1678, 1704], clonidine (Partial agonist) [985, 1678, 1704], brimonidine[985, 1339, 1678, 1704], apraclonidine [1519], guanabenz [79], guanfacine (Partial agonist) [985, 1342] dexmedetomidine [985, 1339, 1678, 1704], clonidine (Partial agonist) [985, 1678, 1704], brimonidine (Partial agonist) [985, 1678, 1704], guanabenz [79], guanfacine[985] dexmedetomidine [985, 1678, 1704], brimonidine (Partial agonist) [985, 1339, 1678, 1704], apraclonidine [1519], guanfacine (Partial agonist) [985], guanabenz [79]
Selective agonists oxymetazoline (Partial agonist) [985, 1339, 2169]
Antagonists yohimbine (pKi 8.4–9.2) [276, 487, 2169] yohimbine (pKi 7.9–8.9) [276, 487, 2169], phenoxybenzamine (pKi 8.5) [2280], tolazoline (pKi 5.5) [985] yohimbine (pKi 8.5–9.5) [276, 487, 2169], WB 4101 (pKi 8.4–9.4) [276, 487, 2169], spiroxatrine (pKi 9) [2169], mirtazapine (pKi 7.7) [593], tolazoline (pKi 5.4) [985]
Selective antagonists BRL 44408 (pKi 8.2–8.8) [2169, 2405] imiloxan (pKi 7.3) [1443] – Rat JP1302 (pKB 7.8) [1855]
Labelled ligands [3H]MK-912 (Antagonist) (pKd 10.1) [2169]

Comments

ARC-239 and prazosin show selectivity for α2B- and α2C-adrenoceptors over α2A-adrenoceptors.Oxymetazoline is a reduced efficacy imidazoline agonist but also binds to non-GPCR binding sites for imidazolines, classified as I1, I2 and I3 sites [444]; catecholamines have a low affinity, while rilmenidine and moxonidine are selective ligands evoking hypotensive effects in vivo. I1-imidazoline receptors cause central inhibition of sympathetic tone, I2-imidazoline receptors are an allosteric binding site on monoamine oxidase B, and I3-imidazoline receptors regulate insulin secretion from pancreatic β-cells. α2A-adrenoceptor stimulation reduces insulin secretion from β-islets [2375], with a polymorphism in the 5’-UTR of the ADRA2A gene being associated with increased receptor expression in β-islets and heightened susceptibility to diabetes [1821]. α2A- and α2C-adrenoceptors form homodimers [1990]. Heterodimers between α2A- and either the α2C-adrenoceptor or μ opioid peptide receptor exhibit altered signalling and trafficking properties compared to the individual receptors [1990, 2099, 2217]. Signalling by α2-adrenoceptors is primarily via Gi/o, although the α2A-adrenoceptor also couples to Gs [538]. Imidazoline compounds display bias relative to each other at the α2A-adrenoceptor [1670]. The noradrenaline reuptake inhibitor desipramine acts directly on the α2A-adrenoceptor to promote internalisation via recruitment of arrestin [421].

Adrenoceptors, β

β-Adrenoceptors are activated by the endogenous agonists (-)-adrenaline and (-)-noradrenaline. Isoprenaline is selective for β-adrenoceptors relative to α1- and α2-adrenoceptors, while propranolol (pKi 8.2-9.2) and cyanopindolol (pKi 10.011.0) are relatively β1 and β2 adrenoceptor-selective antagonists. (-)-noradrenaline, xamoterol and (-)-Ro 363 show selectivity for β1- relative to β2-adrenoceptors. Pharmacological differences exist between human and mouse β3-adrenoceptors, and the ’rodent selective’ agonists BRL 37344 and CL316243 have low efficacy at the human β3-adrenoceptor whereas CGP 12177 and L 755507 activate human β3-adrenoceptors [88]. β3-Adrenoceptors are resistant to blockade by propranolol, but can be blocked by high concentrations of bupranolol. SR59230A has reasonably high affinity at β3-adrenoceptors, but does not discriminate well between the three β- subtypes whereas L 755507 is more selective. [125I]-cyanopindolol, [125I]-hydroxy benzylpindolol and [3H]-alprenolol are high affinity radioligands that label β1- and β2- adrenoceptors and β3-adrenoceptors can be labelled with higher concentrations (nM) of [125I]-cyanopindolol together with β1- and β2-adrenoceptor antagonists. [3H]-L748337 is a β3-selective radioligand [2197]. Fluorescent ligands such as BODIPY-TMR-CGP12177 can be used to track βadrenoceptors at the cellular level [8]. Somewhat selective β1adrenoceptor agonists (denopamine, dobutamine) are used short term to treat cardiogenic shock but, chronically, reduce survival. β1-Adrenoceptor-preferring antagonists areused totreathypertension (atenolol, betaxolol, bisoprolol, metoprolol and nebivolol), cardiac arrhythmias (atenolol, bisoprolol, esmolol) and cardiac failure (metoprolol, nebivolol). Cardiac failure is also treated with carvedilol that blocks β1- and β2-adrenoceptors, as well as α1-adrenoceptors. Short (salbutamol, terbutaline) and long (formoterol, salmeterol) acting β2-adrenoceptor-selective agonists are powerful bronchodilators used to treat respiratory disorders. Many first generation β-adrenoceptor antagonists (propranolol) block both β1- and β2-adrenoceptors and there are no β2adrenoceptor-selective antagonists used therapeutically. The β3-adrenoceptor agonist mirabegron is used to control overactive bladder syndrome.

Nomenclature β1-adrenoceptor β2-adrenoceptor β3-adrenoceptor
HGNC, UniProt ADRB1, P08588 ADRB2, P07550 ADRB3, P13945
Potency order of endogenous ligands (-)-noradrenaline > (-)-adrenaline (-)-adrenaline > (-)-noradrenaline (-)-noradrenaline = (-)-adrenaline
Endogenous agonists (-)-adrenaline [633, 891], (-)-noradrenaline [633, 891], noradrenaline [633] (-)-adrenaline [633, 891, 982], (-)-noradrenaline [633, 891] (-)-noradrenaline [891, 1720, 2044], (-)-adrenaline [891]
Agonists pindolol (Partial agonist) [1159], isoprenaline [633, 1874], dobutamine (Partial agonist) [956] pindolol (Partial agonist) [1159], arformoterol [40], isoprenaline [1874], ephedrine (Partial agonist) [982] carazolol [1431]
Selective agonists (-)-Ro 363 [1472], xamoterol (Partial agonist) [956], denopamine (Partial agonist) [956, 2066] formoterol [94], salmeterol [94], zinterol [94], vilanterol [1737], procaterol [94], indacaterol [123], fenoterol [65], salbutamol (Partial agonist) [96, 956], terbutaline (Partial agonist) [96], orciprenaline [2014] L 755507 [94], L742791 [2277], mirabegron [2089], CGP 12177 (Partial agonist) [177, 1319, 1431, 1472], SB251023 [936] – Mouse, BRL 37344[177, 505, 891, 1431], CL316243 [2372]
Antagonists carvedilol (pKi 9.5) [297], bupranolol (pKi 7.3–9) [297, 1319], SR59230A (pKi 8.6) [297], levobunolol (pKi 8.4) [79], labetalol (pKi 8.2) [79], metoprolol (pKi 7–7.6) [96, 297, 891, 1319], esmolol (pKi 6.9) [79], nadolol (pKi 6.9) [297], practolol (pKi 6.1–6.8) [96, 1319], propafenone (pKi 6.7) [79], sotalol (pKi 6.1) [79] carvedilol (pKi 9.4–9.9) [96, 297], timolol (pKi 9.7) [96], propranolol (pKi 9.1–9.5) [96, 99, 956, 1319], SR59230A (pKi 9.3) [297], levobunolol (pKi 9.3) [79], bupranolol (pKi 8.3–9.1) [297, 1319], alprenolol (pKi 9) [96], nadolol (pKi 7–8.6) [96, 297], labetalol (pKi 8) [79], propafenone (pKi 7.4) [79], sotalol (pKi 6.5) [79] SR59230A (pKi 6.9–8.4) [297, 471, 891], bupranolol (pKi 6.8–7.3) [177, 297, 1319, 1431], propranolol (pKi 6.3–7.2) [1319, 1720], levobunolol (pKi 6.8) [1720]
Selective antagonists CGP 20712A (pKi 8.5–9.2) [96, 297, 1319], levobetaxolol (pKi 9.1) [1942], betaxolol (pKi 8.8) [1319], nebivolol (pIC50 8.1–8.7) [1669] – Rabbit, atenolol (pKi 6.7–7.6) [96, 1021, 1319], acebutolol (pKi 6.4) [79] ICI 118551 (Inverse agonist) (pKi 9.2–9.5) [96, 99, 1319] L-748337 (pKi 8.4) [297], L748328 (pKi 8.4) [297]
Labelled ligands [125I]ICYP (Antagonist) (pKd 10.4–11.3) [956, 1319, 1874] [125I]ICYP (Antagonist) (pKd 11.1) [1319, 1874] [125I]ICYP (Agonist, Partial agonist) [1319, 1472, 1720, 1874, 2044]
Comments The agonists indicated have less than two orders of magnitude selectivity [94]. Agonist SB251023 has a pEC50 of 6.9 for the splice variant of the mouse β3 receptor, β3b [936].

Comments

[125I]ICYP can be used to define β1- or β2adrenoceptors when conducted in the presence of a β1- or β2adrenoceptor-selective antagonist. A fluorescent analogue of CGP 12177 can be used to study β2-adrenoceptors in living cells [97]. [125I]ICYP at higher (nM) concentrations can be used to label β3-adrenoceptors in systems with few if any other β-adrenoceptor subtypes. The β3-adrenoceptor has an intron in the coding region, but splice variants have only been described for the mouse [576], where the isoforms display different signalling characteristics [936]. There are 3 β-adrenoceptors in turkey (termed the tβ, tβ3c and tβ4c) that have a pharmacology that differs from the human β-adrenoceptors [95]. Numerous polymorphisms have been described for the β-adrenoceptors; some are associated with signalling and trafficking, altered susceptibility to disease and/or altered responses to pharmacotherapy [1279]. All β-adrenoceptors couple to Gs (activating adenylyl cyclase and elevating cAMP levels), but also activate Gi and β-arrestin-mediated signalling. Many β1- and β2-adrenoceptor antagonists are agonists at β3adrenoceptors (CL316243, CGP 12177 and carazolol). Many ‘antagonists’ of cAMP accumulation, for example carvedilol and bucindolol, weakly activate MAP kinase pathways [98, 577, 644, 645, 1872, 1873] and thus display ’protean agonism’. Bupranolol acts as a neutral antagonist in most systems so far examined. Agonists also display biased signalling at the β2-adrenoceptor via Gs or arrestins [520]. X-ray crystal structures have been described of the agonist bound [2265] and antagonist bound forms of the β1[2266], agonist-bound [363] and antagonist-bound forms of the β2-adrenoceptor [1773, 1820], as well as a fully active agonistbound, Gs protein-coupled β2-adrenoceptor [1774]. Carvedilol and bucindolol bind to a site on the β1-adrenoceptor involving contacts in TM2, 3, and 7 and extracellular loop 2 that may facilitate coupling to arrestins [2266]. Compounds displaying arrestinbiased signalling at the β2-adrenoceptor have a greater effect on the conformation of TM7, whereas full agonists for Gs coupling promote movement of TM5 and TM6 [1302]. Recent studies using NMR spectroscopy demonstrate significant conformational flexibility in the β2-adrenoceptor that is stabilized by both agonist and G proteins highlighting the dynamic nature of interactions with both ligand and downstreamsignalling partners [1090, 1372, 1605]. Such flexibility likely has consequences for our understanding of biased agonism, and for the future therapeutic exploitation of this phenomenon.

Further reading on Adrenoceptors

Baker JG et al. (2011) Evolution of β-blockers: from anti-anginal drugs to ligand-directed signalling. Trends Pharmacol. Sci. 32: 227-34 [PMID:21429598]

Bylund DB et al. (1994) International Union of Pharmacology nomenclature of adrenoceptors. Pharmacol. Rev. 46: 121-136 [PMID:7938162]

Evans BA et al. (2010) Ligand-directed signalling at beta-adrenoceptors. Br. J. Pharmacol. 159: 1022-38 [PMID:20132209]

Jensen BC et al. (2011) Alpha-1-adrenergic receptors: targets for agonist drugs to treat heart failure. J. Mol. Cell. Cardiol. 51: 518-28 [PMID:21118696]

Kobilka BK. (2011) Structural insights into adrenergic receptor function and pharmacology. Trends Pharmacol. Sci. 32: 213-8 [PMID:21414670]

Langer SZ. (2015) a2-Adrenoceptors in the treatment of major neuropsychiatric disorders. Trends Pharmacol. Sci. 36: 196-202 [PMID:25771972]

Michel MC et al. (2015) Selectivity of pharmacological tools: implications for use in cell physiology. A review in the theme: Cell signaling: proteins, pathways and mechanisms. Am. J. Physiol., Cell Physiol. 308: C505-20 [PMID:25631871]

Angiotensin receptors

Overview

The actions of angiotensin II (AGT, P01019) (Ang II) are mediated by AT1 and AT2 receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on Angiotensin receptors [465, 1045]), which have around 30% sequence similarity. The decapeptide angiotensin I (AGT, P01019), the octapeptide angiotensin II (AGT, P01019) and the heptapeptide angiotensin III (AGT, P01019) are endogenous ligands. Losartan, candesartan, telmisartan, etc. are clinically used AT1 receptor blockers.

Nomenclature AT1 receptor AT2 receptor
HGNC, UniProt AGTR1, P30556 AGTR2, P50052
Endogenous agonists angiotensin II (AGT, P01019) [466, 2199], angiotensin III (AGT, P01019) [466], angiotensin IV (AGT, P01019) (Partial agonist) [1222] angiotensin III (AGT, P01019) [432, 466, 2298], angiotensin II (AGT, P01019) [466, 2000, 2298], angiotensin-(1-7) (AGT, P01019) [210]
Agonists [Sar1,Cha4]Ang-II [896, 1464] – Rat
Selective agonists L-162,313 [1687], L-163,101 [2175] CGP42112 [210], [p-aminoPhe6]ang II [466, 2021] – Rat, compound 21 [2214]
Antagonists saprisartan (pKi 9.1) [870] – Rat, 5-oxo-1-2-4-oxadiazol biphenyl (pIC50 8.8) [1583] – Rat, 5-butyl-methyl immidazole carboxylate 30 (pIC50 8.5) [16], LY303336 (pIC50 8.3) [2198], TRV120027 (pKd 7.7) [2220] saralasin (pIC50 9) [371] – Rat
Selective antagonists candesartan (pIC50 9.5–9.7) [2199], eprosartan (pIC50 8.4–8.8) [543], losartan (pIC50 7.4–8.7) [466, 2135], telmisartan (pIC50 8.4) [1417], olmesartan (pIC50 8.1) [1127] PD123177 (pIC50 8.5–9.5) [337, 371, 529] – Rat, EMA401 (pIC50 8.5–9.3) [599, 1800, 1998], PD123319 (pKd 8.7–9.2) [466, 528, 2308]
Labelled ligands [3H]candesartan (Antagonist) (pKd 10.3) [594], [125I][Sar1]Ang-II (Agonist) [591] – Rat, [125I][Sar1,Ile8]Ang-II (Agonist, Partial agonist) [591] – Rat, [3H]eprosartan (Antagonist) (pKd 9.1) [24] – Rat, [3H]losartan (Antagonist) (pKd 8.2) [341] – Rat [125I]CGP42112 (Agonist) [466, 2298, 2299], [125I][Sar1,Ile8]Ang-II (Agonist) [2097] – Rat
Comments Telmisartan and candesartan are also reported to be agonists of PPARγ [2040].

Comments

AT1 receptors are predominantly coupled to Gq/11, however they are also linked to arrestin recruitment and stimulate G protein-independent arrestin signalling [1332]. Most species express a single AGTR1 gene, but two related agtr1a and agtr1b receptor genes are expressed in rodents. The AT2 receptor counteracts several of the growth responses initiated by the AT1 receptors. The AT2 receptor is much less abundant than the AT1 receptor in adult tissues and is upregulated in pathological conditions. AT1 receptor antagonists bearing substituted 4-phenylquinoline moieties have been synthesized, which bind to AT1 receptors with nanomolar affinity and are slightly more potent than losartan in functional studies [300]. The antagonist activity of CGP42112 at the AT2 receptor has also been reported [1596]. The AT1 and bradykinin B2 receptors have been proposed to form a heterodimeric complex [3]. β-Arrestin1 prevents AT1-B2 receptor heteromerization[1756]. There is also evidence for an AT4 receptor that specifically binds angiotensin IV (AGT, P01019) and is located in the brain and kidney. An additional putative endogenous ligand for the AT4 receptor has been described (LVV-hemorphin (HBB, P68871), a globin decapeptide) [1467].

Further reading on Angiotensin receptors

Asada H et al. (2018) Crystal structure of the human angiotensin II type 2 receptor bound to an angiotensin II analog. Nat. Struct. Mol. Biol. 25: 570-576 [PMID:29967536]

Karnik SS et al. (2015) International Union of Basic and Clinical Pharmacology. XCIX. Angiotensin Receptors: Interpreters of Pathophysiological Angiotensinergic Stimuli [corrected]. Pharmacol. Rev. 67: 754-819 [PMID:26315714]

Singh KD et al. (2019) Mechanism of Hormone Peptide Activation of a GPCR: Angiotensin II Activated State of AT_1R Initiated by van der Waals Attraction. J Chem Inf Model 59: 373-385 [PMID:30608150]

Wingler LM et al. (2019) Angiotensin Analogs with Divergent Bias Stabilize Distinct Receptor Conformations. Cell 176: 468-478.e11 [PMID:30639099]

Wingler LM et al. (2019) Distinctive Activation Mechanism for Angiotensin Receptor Revealed by a Synthetic Nanobody. Cell 176: 479-490.e12 [PMID:30639100]

Zhang H et al. (2015) Structure of the Angiotensin receptor revealed by serial femtosecond crystallography. Cell 161: 833-44 [PMID:25913193]

Apelin receptor

Overview

The apelin receptor (nomenclature as agreed by the NC-IUPHAR Subcommittee on the apelin receptor [1713]) responds to apelin, a 36 amino-acid peptide derived initially from bovine stomach. Apelin-36 (APLN, Q9ULZ1), apelin-13 (APLN, Q9ULZ1) and [Pyr1]apelin-13 (APLN, Q9ULZ1) are the predominant endogenous ligands which are cleaved from a 77 amino-acid precursor peptide (APLN, Q9ULZ1) by a so far unidentified enzymatic pathway [2106]. A second family of peptides discovered independently and named Elabela [372] or Toddler, that has little sequence similarity to apelin, is present, and functional at the apelin receptor in the adult cardiovascular system [1668, 2379]. Structure-activity relationship Elabela analogues have been described [1528].

Nomenclature apelin receptor
HGNC, UniProt APLNR, P35414
Potency order of endogenous ligands [Pyr1]apelin-13 (APLN, Q9ULZ1) ≥ apelin-13 (APLN, Q9ULZ1) > apelin-36 (APLN, Q9ULZ1) [584, 2106]
Endogenous agonists apelin-13 (APLN, Q9ULZ1) [584, 909, 1428], apelin receptor early endogenous ligand (APELA, P0DMC3) [483], apelin-17 (APLN, Q9ULZ1) [547, 1428], [Pyr1]apelin-13 (APLN, Q9ULZ1) [1056, 1428], Elabela/Toddler-21 (APELA, P0DMC3) 2378, Elabela/Toddler-32 (APELA, P0DMC3) 2378, apelin-36 (APLN, Q9ULZ1) [584, 909, 1056, 1428], Elabela/Toddler-11 (APELA, Q9ULZ1) 2378
Selective agonists CMF-019 (Biased agonist) [1781], MM07 (Biased agonist) [226]
Antagonists MM54 (pKi 8.2) [1338]
Labelled ligands [125I][Nle75,Tyr77]apelin-36 (human) (Agonist) [1056], [125I][Glp65Nle75,Tyr77]apelin-13 (Agonist) [909], [125I](Pyr1)apelin-13 (Agonist) [1050], [125I]apelin-13 (Agonist) [584], [3H](Pyr1)[Met(0)11]-apelin-13 (Agonist) [1428]

Comments

Potency order determined for heterologously expressed human apelin receptor (pD2 values range from 9.5 to 8.6). The apelin receptor may also act as a co-receptor with CD4 for isolates of human immunodeficiency virus, with apelin blocking this function [323]. A modified apelin-13 peptide, apelin-13(F13A) was reported to block the hypotensive response to apelin in rat in vivo [1238], however, this peptide exhibits agonist activity in HEK293 cells stably expressing the recombinant apelin receptor [584]. The apelin receptor antagonist, MM54, was reported to suppress tumour growth and increase survival in an intracranial xenograft mouse model of glioblastoma [809].

Further reading on Apelin receptor

Cheng B et al. (2012) Neuroprotection of apelin and its signaling pathway. Peptides 37: 171-3 [PMID:22820556]

Langelaan DN et al. (2009) Structural insight into G-protein coupled receptor binding by apelin. Biochemistry 48: 537-48 [PMID:19123778]

Mughal A et al. (2018) Vascular effects of apelin: Mechanisms and therapeutic potential. Pharmacol. Ther. 190: 139-147 [PMID:29807055]

O’Carroll AM et al. (2013) The apelin receptor APJ: journey from an orphan to a multifaceted regulator of homeostasis. J. Endocrinol. 219: R13-35 [PMID:23943882]

Pitkin SL et al. (2010) International Union of Basic and Clinical Pharmacology. LXXIV. Apelin receptor nomenclature, distribution, pharmacology, and function. Pharmacol. Rev. 62: 331-42 [PMID:20605969]

Yang P et al. (2015) Apelin, Elabela/Toddler, and biased agonists as novel therapeutic agents in the cardiovascular system. Trends Pharmacol. Sci. 36: 560-7 [PMID:26143239]

Bile acid receptor

Overview

The bile acid receptor (GPBA) responds to bile acids produced during the liver metabolism of cholesterol. Selective agonists are promising drugs for the treatment of metabolic disorders, such as type II diabetes, obesity and atherosclerosis.

Nomenclature GPBA receptor
HGNC, UniProt GPBAR1, Q8TDU6
Potency order of endogenous ligands lithocholic acid > deoxycholic acid > chenodeoxycholic acid, cholic acid [1055, 1392]
Selective agonists S-EMCA [1676] – Mouse, betulinic acid [680], oleanolic acid [1871]

Comments

The triterpenoid natural product betulinic acid has also been reported to inhibit inflammatory signalling through the NFκB pathway [2081]. Disruption of GPBA expression is reported to protect from cholesterol gallstone formation [2209]. A new series of 5-phenoxy-1,3-dimethyl-1H-pyrazole-4-carboxamides have been reported as highly potent agonists [1313].

Further reading on Bile acid receptor

Duboc H et al. (2014) The bile acid TGR5 membrane receptor: from basic research to clinical application. Dig Liver Dis 46: 302-12 [PMID:24411485]

Lieu T et al. (2014) GPBA: a GPCR for bile acids and an emerging therapeutic target for disorders of digestion and sensation. Br. J. Pharmacol. 171: 1156-66 [PMID:24111923]

Lefebvre P et al. (2009) Role of bile acids and bile acid receptors in metabolic regulation. Physiol. Rev. 89: 147-91 [PMID:19126757]

van Nierop FS et al. (2017) Clinical relevance of the bile acid receptor TGR5 in metabolism. Lancet Diabetes Endocrinol 5: 224-233 [PMID:27639537]

Bombesin receptors

Overview

Mammalian bombesin (Bn) receptors comprise 3 subtypes: BB1, BB2, BB3 (nomenclature recommended by the NC-IUPHAR Subcommittee on bombesin receptors, [990]). BB1 and BB2 are activated by the endogenous ligands gastrin-releasing peptide (GRP, P07492) (GRP), neuromedin B (NMB, P08949) (NMB) and GRP-(18-27) (GRP, P07492). Bombesin is a tetradecapeptide, originally derived from amphibians. The three Bn receptor subtypes couple primarily to the Gq/11 and G12/13 family of G proteins [990]. Each of these receptors is widely distributed in the CNS and peripheral tissues [723, 990, 1721, 1766, 1866, 2420]. Activation of BB1 and BB2 receptors causes a wide range of physiological/pathophysiogical actions, including the stimulation of normal and neoplastic tissue growth, smoothmuscle contraction, feeding behavior, secretion and many central nervous system effects including regulation of circadian rhythm and mediation of pruritus [990, 991, 992, 1359, 1489,1766]. A physiological role for the BB3 receptor has yet to be fully defined although recently studies suggest an important role in glucose and insulin regulation, metabolic homeostasis, feeding, regulation of body temperature, obesity, diabetes mellitus and growth of normal/neoplastic tissues [723, 1360, 1619, 2345].

Nomenclature BB1 receptor BB2 receptor BB3 receptor
HGNC, UniProt NMBR, P28336 GRPR, P30550 BRS3, P32247
Endogenous agonists neuromedin B (NMB, P08949) [990, 1766, 2166] neuromedin C [2166], gastrin releasing peptide(14-27) (human) [2166]
Selective agonists compound 9g [1398], MK-7725 [373], MK-5046 [1494, 1915], [D-Tyr6,Apa-4Cl11,Phe13,Nle14]bombesin-(6-14) [1376], compound 17c [1397], bag-1 [759], compound 22e [836]
Antagonists D-Nal-Cys-Tyr-D-Trp-Lys-Val-Cys-Nal-NH2 (pIC50 6.2–6.6) [722]
Selective antagonists PD 176252 (pIC50 9.3–9.8) [722], PD 168368 (pIC50 9.3–9.6) [722], dNal-cyc(Cys-Tyr-dTrp-Orn-Val)-Nal-NH2 [D-Phe6, Leu13, Cpa14,ψ13-14]bombesin-(6-14) (pKi 9.8) [722], JMV641 (pIC50 9.3) [2140] – Mouse, [(3-Ph-Pr6), His7,D-Ala11,D-Pro13,ψ13-14),Phe14]bombesin-( (pIC50 9.2) [722, 1231], JMV594 (pIC50 8.9) [1308, 2140] – Mouse, [D-Tpi6, Leu13 ψ(CH2NH)-Leu14]bombesin-(6-14) (pIC50 8.9) [722] bantag-1 (pIC50 8.6–8.7) [759, 1494], ML-18 (pIC50 5.3) [1488] 6-14)
Labelled ligands [125I]BH-NMB (human, mouse, rat) (Agonist), [125I][Tyr4]bombesin (Agonist) [125I][D-Tyr6]bombesin-(6-13)-methyl ester (Selective Antagonist) (pKd 9.3) [1375] – Mouse, [125I][Tyr4]bombesin (Agonist) [144], [125I]GRP (human) (Agonist) [3H]bag-2 (Agonist) [759] – Mouse, [125I][D-Tyr6,β-Ala11,Phe13,Nle14]bombesin-(6-14) (Agonist) [1377, 1494]

Comments

All three human subtypes may be activated by [D-Phe6,β-Ala11,Phe13,Nle14]bombesin-(6-14) [1377]. [D-Tyr6,Apa-4Cl11,Phe13,Nle14]bombesin-(6-14) has more than 200-fold selectivity for BB3 receptors over BB1 and BB2 [1376, 1377, 1766, 1767].

Further reading on Bombesin receptors

González N et al. (2015) Bombesin receptor subtype 3 as a potential target for obesity and diabetes. Expert Opin. Ther. Targets 19: 1153-70 [PMID:26066663]

Jensen RT et al. (2008) International Union of Pharmacology. LXVIII. Mammalian bombesin receptors: nomenclature, distribution, pharmacology, signaling, and functions in normal and disease states. Pharmacol. Rev. 60: 1-42 [PMID:18055507]

Maina T et al. (2017) Theranostic Prospects of Gastrin-Releasing Peptide Receptor-Radioantagonists in Oncology. PET Clin 12: 297-309 [PMID:28576168]

Moreno P et al. (2016) Bombesin related peptides/receptors and their promising therapeutic roles in cancer imaging, targeting and treatment. Expert Opin. Ther. Targets 20: 1055-73 [PMID:26981612]

Qu X et al. (2018) Recent insights into biological functions of mammalian bombesin-like peptides and their receptors. Curr Opin Endocrinol Diabetes Obes 25: 36-41 [PMID:29120926]

Ramos-Álvarez I et al. (2015) Insights into bombesin receptors and ligands: Highlighting recent advances. Peptides 72: 128-44 [PMID:25976083]

Bradykinin receptors

Overview

Bradykinin (or kinin) receptors (nomenclature as agreed by the NC-IUPHAR subcommittee on Bradykinin (kinin) Receptors [1243]) are activated by the endogenous peptides bradykinin (KNG1, P01042) (BK), [des-Arg9]bradykinin (KNG1, P01042), Lys-BK (kallidin (KNG1, P01042)), [des-Arg10]kallidin (KNG1, P01042), [Phospho-Ser6]-Bradykinin, T-kinin (KNG1, P01042) (Ile-SerBK), [Hyp3]bradykinin (KNG1, P01042) and Lys-[Hyp3]-bradykinin (KNG1, P01042). Variation in pharmacology and activity of B1 and B2 receptor antagonists at species orthologs has been documented. Icatibant (Hoe140, Firazir) is approved in North America and Europe for the treatment of acute attacks of hereditary angioedema.

Nomenclature B1 receptor B2 receptor
HGNC, UniProt BDKRB1, P46663 BDKRB2, P30411
Potency order of endogenous ligands [des-Arg10]kallidin (KNG1, P01042) > [des-Arg9]bradykinin (KNG1, P01042) = kallidin (KNG1, P01042) > bradykinin (KNG1, P01042) kallidin (KNG1, P01042) > bradykinin (KNG1, P01042) [des-Arg9]bradykinin (KNG1, P01042), [des-Arg10]kallidin (KNG1, P01042)
Endogenous agonists [des-Arg10]kallidin (KNG1, P01042) [80, 118, 714, 1012] bradykinin (KNG1, P01042)
Selective agonists NG29 [1879], [Sar,D-Phe8,des-Arg9]bradykinin [1012] NG291 [282, 1880], [Hyp3,Tyr(Me)8]BK, [Phe8,ψ(CH2-NH)Arg9]BK, labradimil [282, 1880]
Selective antagonists B-9958 (pKi 9.2–10.3) [689, 1784], [Leu9,des-Arg10]kallidin (pKi 9.1–9.3) [80, 118], SSR240612 (pKi 9.1–9.2) [732], R-954 (pA2 8.6) [715], R-715 (pA2 8.5) [713] icatibant (pKi 10.2) [43], FR173657 (pA2 8.2) [1814], anatibant (pKi 8.2) [1742]
Labelled ligands [125I]Hpp-desArg10HOE140 (pKd 10), [3H]Lys-[des-Arg9]BK (Agonist), [3H]Lys-[Leu8][des-Arg9]BK (Antagonist) [3H]BK (human, mouse, rat) (Agonist) [2318] – Mouse, [3H]NPC17731 (Antagonist) (pKd 9.1–9.4) [2423, 2424], [125I][Tyr8]bradykinin (Agonist)

Further reading on Bradykinin receptors

Campos MM et al. (2006) Non-peptide antagonists for kinin B1 receptors: new insights into their therapeutic potential for the management of inflammation and pain. Trends Pharmacol. Sci. 27: 646-51 [PMID:17056130]

Duchene J et al. (2009) The kinin B(1) receptor and inflammation: new therapeutic target for cardiovascular disease. Curr Opin Pharmacol 9: 125-31 [PMID:19124274]

Marceau F et al. (2004) Bradykinin receptor ligands: therapeutic perspectives. Nat Rev Drug Discov 3: 845-52 [PMID:15459675]

Paquet JL et al. (1999) Pharmacological characterization of the bradykinin B2 receptor: inter-species variability and dissociation between binding and functional responses. Br. J. Pharmacol. 126: 1083-90 [PMID:10204994]

Thornton E et al. (2010) Kinin receptor antagonists as potential neuroprotective agents in central nervous system injury. Molecules 15: 6598-618 [PMID:20877247]

Whalley ET et al. (2012) Discovery and therapeutic potential of kinin receptor antagonists. Expert Opin Drug Discov 7: 1129-48 [PMID:23095011]

Calcitonin receptors

Overview

This receptor family comprises a group of receptors for the calcitonin/CGRP family of peptides. The calcitonin (CT), amylin (AMY), calcitonin gene-related peptide (CGRP) and adrenomedullin (AM) receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on CGRP, AM, AMY, and CT receptors [830, 1732]) are generated by the genes CALCR (which codes for the CT receptor) and CALCRL (which codes for the calcitonin receptor-like receptor, CLR, previously known as CRLR). Their function and pharmacology are altered in the presence of RAMPs (receptor activity-modifying proteins), which are single TM domain proteins of ca. 130 amino acids, identified as a family of three members; RAMP1, RAMP2 and RAMP3. There are splice variants of the CT receptor; these in turn produce variants of the AMY receptor [1732], some of which can be potently activated by CGRP. The endogenous agonists are the peptides calcitonin (CALCA, P01258), α-CGRP (CALCA, P06881) (formerly known as CGRP-I), β-CGRP (CALCB, P10092) (formerly known as CGRP-II), amylin (IAPP, P10997) (occasionally called islet-amyloid polypeptide, diabetes-associated polypeptide), adrenomedullin (ADM, P35318) and adrenomedullin 2/intermedin (ADM2, Q7Z4H4). There are species differences in peptide sequences, particularly for the CTs. CTR-stimulating peptide {Pig} (CRSP) is another member of the family with selectivity for the CT receptor but it is not expressed in humans [1047]. Olcegepant (also known as BIBN4096BS, pKi10.5) and telcagepant (also known as MK0974, pKi9) are the most selective antagonists available, showing selectivity for CGRP receptors, with a particular preference for those of primate origin. CLR (calcitonin receptor-like receptor) by itself binds no known endogenous ligand, but in the presence of RAMPs it gives receptors for CGRP, adrenomedullin and adrenomedullin 2/intermedin.

Nomenclature CT receptor AMY1 receptor AMY2 receptor AMY3 receptor
HGNC, UniProt CALCR, P30988
Subunits RAMP1 (Accessory protein), CT receptor CT receptor, RAMP2 (Accessory protein) CT receptor, RAMP3 (Accessory protein)
Potency order of endogenous ligands calcitonin (salmon) ≥ calcitonin (CALCA, P01258) ≥ amylin (IAPP, P10997), α-CGRP (CALCA, P06881), β-CGRP (CALCB, P10092) > adrenomedullin (ADM, P35318), adrenomedullin 2/intermedin (ADM2, Q7Z4H4) calcitonin (salmon) ≥ amylin (IAPP, P10997) ≥α-CGRP (CALCA, P06881), β-CGRP (CALCB, P10092) > adrenomedullin 2/intermedin (ADM2, Q7Z4H4) ≥ calcitonin (CALCA, P01258) > adrenomedullin (ADM, P35318) Poorly defined calcitonin (salmon) ≥ amylin (IAPP, P10997) > α-CGRP (CALCA, P06881),β-CGRP (CALCB, P10092) ≥ adrenomedullin 2/intermedin (ADM2, Q7Z4H4) ≥ calcitonin (CALCA, P01258) > adrenomedullin (ADM, P35318)
Endogenous agonists calcitonin (CALCA, P01258) [35, 68, 827, 1183, 1263, 1517] α-CGRP (CALCA, P06881) [827, 1182, 1183, 1263, 2241], amylin (IAPP, P10997) [705], β-CGRP (CALCB, P10092) amylin (IAPP, P10997) [705] amylin (IAPP, P10997) [705]
Sub/family-selective agonists pramlintide [705] pramlintide [705] pramlintide [705]
Sub/family-selective antagonists CT-(8-32) (salmon) (pKd 9) [874], AC187 (pKi 7.2) [827] AC187 (pKi 8) [827], CT-(8-32) (salmon) (pKi 7.8) [827], olcegepant (pKd 7.2) [2241] CT-(8-32) (salmon) (pKi 7.9) [827], AC187 (pKi 7.7) [827]
Labelled ligands [125I]CT (human) (Agonist), [125I]CT (salmon) (Agonist) [125I]αCGRP (human) (Agonist), [125I]BH-AMY (rat, mouse) (Agonist) [125I]BH-AMY (rat, mouse) (Agonist) [125I]BH-AMY (rat, mouse) (Agonist)
Nomenclature calcitonin receptor-like receptor CGRP receptor AM1 receptor AM2 receptor
HGNC, UniProt CALCRL, Q16602
Subunits calcitonin receptor-like receptor, RAMP1 (Accessory protein) calcitonin receptor-like receptor, RAMP2 (Accessory protein) calcitonin receptor-like receptor, RAMP3 (Accessory protein)
Potency order of endogenous ligands α-CGRP (CALCA, P06881), β-CGRP (CALCB, P10092) > adrenomedullin (ADM, P35318) ≥ adrenomedullin 2/intermedin (ADM2, Q7Z4H4) > amylin (IAPP, P10997) ≥ calcitonin (salmon) adrenomedullin (ADM, P35318) > adrenomedullin 2/intermedin (ADM2, Q7Z4H4) >α-CGRP (CALCA, P06881), β-CGRP (CALCB, P10092), amylin (IAPP, P10997) > calcitonin (salmon) adrenomedullin (ADM, P35318) ≥ adrenomedullin 2/intermedin (ADM2, Q7Z4H4) ≥α-CGRP (CALCA, P06881), β-CGRP (CALCB, P10092) > amylin (IAPP, P10997) > calcitonin (salmon)
Endogenous agonists β-CGRP (CALCB, P10092) [23, 1426], α-CGRP (CALCA, P06881) [23, 1426] adrenomedullin (ADM, P35318) [23, 1426] adrenomedullin (ADM, P35318) [23, 623]
Antagonists olcegepant (pKi 10.7–11) [512, 828, 829, 1022, 1368], telcagepant (pKi 9.1) [1857]
Selective antagonists AM-(22-52) (human) (pKi 7–7.8) [829] AM-(22-52) (human)
Labelled ligands [125I]αCGRP (human) (Agonist), [125I]αCGRP (mouse, rat) (Agonist) [125I]AM (rat) (Agonist) [125I]AM (rat) (Agonist)

Comments

It is important to note that a complication with the interpretation of pharmacological studies with AMY receptors in transfected cells is that most of this work has likely used a mixed population of receptors, encompassing RAMP-coupled CTR as well as CTR alone. This means that although in binding assays human calcitonin (CALCA, P01258) has low affinity for 125I-AMY binding sites, cells transfected with CTR and RAMPs can display potent CT functional responses. Transfection of human CTR with any RAMP can generate receptors with a high affinity for both salmon CT and AMY and varying affinity for different antagonists [388, 827, 828]. The major human CTR splice variant (hCT(a), which does not contain an insert) with RAMP1 (i.e. the AMY1(a) receptor) has a high affinity for CGRP [2241], unlike hCT(a)-RAMP3 (i.e. AMY3(a) receptor) [388, 827]. However, the AMY receptor phenotype is RAMP-type, splice variant and cell-line-dependent [1495, 1750, 2134]. Emerging data suggests that AMY1 could be a second CGRP receptor [826].

The ligands described have limited selectivity. Adrenomedullin has appreciable affinity for CGRP receptors. CGRP can show significant cross-reactivity at AMY receptors and AM2 receptors. Adrenomedullin 2/intermedin also has high affinity for the AM2 receptor [903]. CGRP-(8-37) acts as an antagonist of CGRP (pKi 8) and inhibits some AM and AMY responses (pKi 6-7). It is weak at CT receptors. HumanAM-(22-52)has some selectivity towardsAM receptors, but with modest potency (pKi 7), limiting its use [829]. Olcegepant shows the greatest selectivity between receptors but still has significant affinity for AMY1 receptors [2241].

Gs is a prominent route for effector coupling for CLR and CTR but other pathways (e.g. Ca2+, ERK, Akt), and G proteins can be activated [2240]. There is evidence that CGRP-RCP (a 148 amino-acid hydrophilic protein, ASL (P04424) is important for the coupling of CLR to adenylyl cyclase [578].

[125I]-Salmon CT is the most common radioligand for CT receptors but it has high affinity for AMY receptors and is also poorly reversible.

Further reading on Calcitonin receptors

Hay DL et al. (2018) Update on the pharmacology of calcitonin/CGRP family of peptides: IUPHAR Review 25. Br. J. Pharmacol. 175: 3-17 [PMID:29059473]

Russell FA et al. (2014) Calcitonin gene-related peptide: physiology and pathophysiology. Physiol. Rev. 94: 1099-142 [PMID:25287861]

Hay DL et al. (2016) Receptor Activity-Modifying Proteins (RAMPs): New Insights and Roles. Annu. Rev. Pharmacol. Toxicol. 56: 469-87 [PMID:26514202]

Russo AF. (2015) Calcitonin gene-related peptide (CGRP): a new target for migraine. Annu. Rev. Pharmacol. Toxicol. 55: 533-52 [PMID:25340934]

Kato J et al. (2015) Bench-to-bedside pharmacology of adrenomedullin. Eur. J. Pharmacol. 764: 140-8 [PMID:26144371]

Calcium-sensing receptor

Overview

The calcium-sensing receptor (CaS, provisional nomenclature as recommended by NC-IUPHAR [612]) responds to multiple endogenous ligands, including extracellular calcium and other divalent/trivalent cations, polyamines and polycationic peptides, L-amino acids (particularly L-Trp and L-Phe), glutathione and various peptide analogues, ionic strength and extracellular pH (reviewed in [1228]). While divalent/trivalent cations, polyamines and polycations are CaS receptor agonists [252, 1754], L-amino acids, glutamyl peptides, ionic strength and pH are allosteric modulators of agonist function [411, 612, 885, 1752, 1753]. Indeed, L-amino acids have been identified as "co-agonists", with both concomitant calcium and L-amino acid binding required for full receptor activation [682, 2416]. The sensitivity of the CaS receptor to primary agonists is increased by elevated extracellular pH [295] or decreased extracellular ionic strength [1753]. This receptor bears no sequence or structural relation to the plant calcium receptor, also called CaS.

Nomenclature CaS receptor
HGNC, UniProt CASR, P41180
Amino-acid rank order of potency L-phenylalanine, L-tryptophan, L-histidine > L-alanine > L-serine, L-proline, L-glutamic acid > L-aspartic acid (not L-lysine, L-arginine, L-leucine and L-isoleucine) [411]
Cation rank order of potency Gd3+ > Ca2+ > Mg2+ [252]
Glutamyl peptide rank order of potency S-methylglutathione ≈ γGlu-Val-Gly > glutathione >γGlu-Cys [243, 1621, 2256]
Polyamine rank order of potency spermine > spermidine > putrescine [1754]
Allosteric modulators ATF 936 (Negative) (pIC50 8.9) [2302], encaleret (Negative) (pIC50 7.9) [1956], SB-423562 (Negative) (pIC50 7.1) [1176], ronacaleret (Negative) (pIC50 6.5–6.8) [101], NPS 2143 (Negative) (pKB 6.2–6.7) [459, 1226, 1229], cinacalcet (Positive) (pKB 5.9–6.6) [414, 459, 1226, 1229], tecalcet (Positive) (pKB 6.2–6.6) [414, 459], AC265347 (Positive) (pKB 6.3–6.4) [414, 1226], calhex 231 (Negative) (pIC50 6.4) [1699], calindol (Positive) (pKB 6.3) [414]

Comments

The CaS receptor has a number of physiological functions, but it is best known for its central role in parathyroid and renal regulation of extracellular calcium homeostasis [798]. This is seen most clearly in patients with loss-of-function CaS receptor mutations who develop familial hypocalciuric hypercalcaemia (heterozygous mutations) or neonatal severe hyperparathyroidism (heterozygous, compound heterozygous or homozygous mutations) [798] and in Casr null mice [339, 885], which exhibit similar increases in PTH secretion and blood calcium levels. Gain-of-function CaS mutations are associated with autosomal dominant hypocalcaemia and Bartter syndrome type V [798].

The CaS receptor primarily couples to Gq/11, G12/13 and Gi/o [459, 693, 922, 2124], but in some cell types can couple to Gs [1370]. However, the CaS receptor can form heteromers with Class C GABAB [340, 362] and mGlu1/5 receptors [651], which may introduce further complexity in its signalling capabilities.

Multiple other small molecule chemotypes are positive and negative allosteric modulators of the CaS receptor [1078, 1565]. Further, etelcalcetide is a novel peptide positive allosteric modulator of the receptor [2243]. Agonists and positive allosteric modulators of the CaS receptor are termed Type I and II calcimimetics, respectively, and can suppress parathyroid hormone (PTH (PTH, P01270)) secretion [1567]. Negative allosteric modulators are called calcilytics and can act to increase PTH (PTH, P01270) secretion [1566].

Where functional pKB values are provided for allosteric modulators, this refers to ligand affinity determined in an assay that measures a functional readout of receptor activity (i.e. a receptor signalling assay), as opposed to affinity determined in a radioligand binding assay. The functional pKB may differ depending on the signalling pathway studied. Consult the ’More detailed page’ for the assay description, as well as other functional readouts.

Further reading on Calcium-sensing receptor

Brown EM. (2013) Role of the calcium-sensing receptor in extracellular calcium homeostasis. Best Pract. Res. Clin. Endocrinol. Metab. 27: 333-43 [PMID:23856263]

Hannan FM et al. (2018) The calcium-sensing receptor in physiology and in calcitropic and noncal citropic diseases. Nat Rev Endocrinol 15: 33-51 [PMID:30443043]

Conigrave AD et al. (2013) Calcium-sensing receptor (CaSR): pharmacological properties and signaling pathways. Best Pract. Res. Clin. Endocrinol. Metab. 27: 315-31 [PMID:23856262]

Nemeth EF et al. (2018) Discovery and Development of Calcimimetic and Calcilytic Compounds. Prog Med Chem 57: 1-86 [PMID:29680147]

Cannabinoid receptors

Overview

Cannabinoid receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on Cannabinoid Receptors [1692]) are activated by endogenous ligands that include N-arachidonoylethanolamine (anandamide), N-homo-γ-linolenoylethanolamine, N-docosatetra-7,10,13,16-enoylethanolamine and 2-arachidonoylglycerol. Potency determinations of endogenous agonists at these receptors are complicated by the possibility of differential susceptibility of endogenous ligands to enzymatic conversion [38].

There are currently three licenced cannabinoid medicines each of which contains a compound that can activate CB1 and CB2 receptors [1690]. Two of these medicines were developed to suppress nausea and vomiting produced by chemotherapy. These are nabilone (Cesamet®), a synthetic CB1/CB2 receptor agonist, and synthetic Δ9-tetrahydrocannabinol (Marinol®; dronabinol), which can also be used as an appetite stimulant. The third medicine, Sativex®, contains mainly Δ9-tetrahydrocannabinol and cannabidiol, both extracted from cannabis, and is used to treat multiple sclerosis and cancer pain.

Nomenclature CB1 receptor CB2 receptor
HGNC, UniProt CNR1, P21554 CNR2, P34972
Agonists HU-210 [590, 1960], CP55940 [590, 1824, 1960], WIN55212-2 [590, 1959, 1960], Δ9-tetrahydrocannabinol (Partial agonist) [590, 1960], cannabinol (Partial agonist) [590, 1960] HU-210 [590, 1796, 1960], WIN55212-2 [590, 1959, 1960], CP55940 [590, 1824, 1960], 9-tetrahydrocannabinol (Partial agonist) [121, 590, 1796, 1960]
Selective agonists arachidonyl-2-chloroethylamide [872] – Rat, arachidonylcyclopropylamide [872] – Rat, O-1812 [489] – Rat, R-(+)-methanandamide [1073] – Rat JWH-133 [930, 1691], L-759,633 [663, 1824], AM1241 [2381], L-759,656 [663, 1824], HU-308 [806]
Selective antagonists rimonabant (pKi 7.9–8.7) [589, 590, 1804, 1835, 1960], AM6545 (pKi 8.5) [217], AM251 (pKi 8.1) [1196] – Rat, AM281 (pKi 7.9) [1195] – Rat, LY320135 (pKi 6.9) [589] SR144528 (pKi 8.3–9.2) [1805, 1824], AM-630 (pKi 7.5) [1824]
Allosteric modulators GAT100 (Negative) (pEC50 7.7) [1172], ZCZ011 (Positive) (pEC50 6.3) [943] – Mouse, GAT211 (Positive) [1205], cannabidiol (Negative) [1204] pepcan-12 (Positive) (pKi ∼7.3) [1701], compound C2 (Positive) [643]
Labelled ligands [3H]rimonabant (Antagonist) (pKd 8.9–10) [228, 880, 1025, 1698, 1806, 1972, 2118] – Rat

Comments

Both CB1 and CB2 receptors may be labelled with [3H]CP55940 (0.5 nM;[1960]) and [3H]WIN55212-2 (2-2.4 nM; [1987, 2013]). Anandamide is also an agonist at vanilloid receptors (TRPVl)and PPARs [1608, 2444]. There is evidence for an allosteric site on the CB1 receptor [1735]. All of the compounds listed as antagonists behave as inverse agonists in some bioassay systems [1692]. For some cannabinoid receptor ligands, additional pharmacological targets that include GPR55 and GPR119 have been identified [1692]. Moreover, GPR18, GPR55 and GPR119, although showing little structural similarity to CB1 and CB2 receptors, respond to endogenous agents that are structurally similar to the endogenous cannabinoid ligands [1692].

Further reading on Cannabinoid receptors

Howlett AC et al. (2002) International Union of Pharmacology. XXVII. Classification of cannabinoid receptors. Pharmacol. Rev. 54: 161-202 [PMID:12037135]

Pertwee RG et al. (2010) International Union of Basic and Clinical Pharmacology. LXXIX. Cannabinoid receptors and their ligands: beyond CB_1 and CB_2. Pharmacol. Rev. 62: 588-631 [PMID:21079038]

Pertwee RG. (2010) Receptors and channels targeted by synthetic cannabinoid receptor agonists and antagonists. Curr. Med. Chem. 17: 1360-81 [PMID:20166927]

Chemerin receptors

Overview

Nomenclature for the chemerin receptors is presented as recommended by NC-IUPHAR [455, 1065]). The chemoattractant protein and adipokine, chemerin (RARRES2, Q99969), has been shown to be the endogenous ligand for both chemerin family receptors. Chemerin1 was the founding family member, and when GPR1 was de-orphanised it was re-named Chermerin2 [1065]. Chemerin1 is also activated by the lipid-derived, antiinflammatory ligand resolvin E1 (RvE1), which is formed via the sequential metabolism of EPA by aspirin-modified cyclooxygenase and lipoxygenase [66, 67]. In addition, two GPCRs for resolvin D1 (RvD1) have been identified: FPR2/ALX, the lipoxin A4 receptor, and GPR32, an orphan receptor [1153].

Nomenclature chemerin receptor 1 chemerin receptor 2
Common abbreviation Chemerin1 Chemerin2
HGNC, UniProt CMKLR1, Q99788 GPR1, P46091
Potency order of endogenous ligands resolvin E1 > chemerin C-terminal peptide > 18R-HEPE > EPA [66]
Endogenous agonists chemerin (RARRES2, Q99969) [109]
Selective agonists resolvin E1
Labelled ligands [3H]resolvin E1 (Agonist) [66, 67]
Comments Reported to act as a co-receptor for HIV [1952]. See review [455] for discussion of pairing with chemerin.

Comments

CCX832 (structure not disclosed) is a selective antagonist, pKi=9.2 [1066].

Further reading on Chemerin receptors

Kennedy AJ et al. (2018) International Union of Basic and Clinical Pharmacology CIII: Chemerin Receptors CMKLR1 (Chemerin1) and GPR1 (Chemerin2) Nomenclature, Pharmacology, and Function. Pharmacol. Rev. 70: 174-196 [PMID:29279348]

Shin WJ et al. (2018) Mechanisms and Functions of Chemerin in Cancer: Potential Roles in Therapeutic Intervention. Front Immunol 9: 2772 [PMID:30555465]

Chemokine receptors

Overview

Chemokine receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on Chemokine Receptors [90, 1524, 1525]) comprise a large subfamily of 7TM proteins that bind one or more chemokines, a large family of small cytokines typically possessing chemotactic activity for leukocytes. Additional hematopoietic and non-hematopoietic roles have been identified for many chemokines in the areas of embryonic development, immune cell proliferation, activation and death, viral infection, and as antibiotics, among others. Chemokine receptors can be divided by function into two main groups: G protein-coupled chemokine receptors, which mediate leukocyte trafficking, and "Atypical chemokine receptors", which may signal through non-G protein-coupled mechanisms and act as chemokine scavengers to downregulate inflammation or shape chemokine gradients [90].

Chemokines in turn can be divided by structure into four subclasses by the number and arrangement of conserved cysteines. CC (also known as β-chemokines; n= 28), CXC (also known as α-chemokines; n= 17) and CX3C (n= 1) chemokines all have four conserved cysteines, with zero, one and three amino acids separating the first two cysteines respectively. C chemokines (n= 2) have only the second and fourth cysteines found in other chemokines. Chemokines can also be classified by function into homeostatic and inflammatory subgroups. Most chemokine receptors are able to bind multiple high-affinity chemokine ligands, but the ligands for a given receptor are almost always restricted to the same structural subclass. Most chemokines bind to more than one receptor subtype. Receptors for inflammatory chemokines are typically highly promiscuous with regard to ligand specificity, and may lack a selective endogenous ligand. G protein-coupled chemokine receptors are named acccording to the class of chemokines bound, whereas ACKR is the root acronym for atypical chemokine receptors [91]. There can be substantial cross-species differences in the sequences of both chemokines and chemokine receptors, and in the pharmacology and biology of chemokine receptors. Endogenous and microbial non-chemokine ligands have also been identified for chemokine receptors. Many chemokine receptors function as HIV co-receptors, but CCR5 is the only one demonstrated to play an essential role in HIV/AIDS pathogenesis. The tables include bothstandard chemokine receptor names [2401] and aliases.

Nomenclature CCR1 CCR2 CCR3
HGNC, UniProt CCR1, P32246 CCR2, P41597 CCR3, P51677
Endogenous agonists CCL3 (CCL3, P10147) [375, 406, 862, 2443], CCL23 (CCL23, P55773) [375], CCL5 (CCL5, P13501) [406, 862], CCL7 (CCL7, P80098) [375, 775], CCL15 (CCL15, Q16663) [423], CCL14 (CCL14, Q16627) [375], CCL13 (CCL13, Q99616), CCL8 (CCL8, P80075) CCL2 (CCL2, P13500) [423, 1335, 1461, 1658, 2167], CCL13 (CCL13, Q99616) [1335, 2167], CCL7 (CCL7, P80098) [423, 1335, 2167], CCL11 (CCL11, P51671) (Partial agonist) [1335, 1658], CCL16 (CCL16, O15467) CCL13 (CCL13, Q99616) [1505, 2167], CCL24 (CCL24, O00175) [1505, 1658], CCL5 (CCL5, P13501) [449], CCL7 (CCL7, P80098) [449], CCL11 (CCL11, P51671) [531, 1108, 1505, 1849, 2167], CCL26 (CCL26, Q9Y258) [1108, 1505, 1658], CCL15 (CCL15, Q16663) [423], CCL28 (CCL28, Q9NRJ3), CCL8 (CCL8, P80075)
Agonists CCL11 {Mouse} [449]
Endogenous antagonists CCL4 (CCL4, P13236) (pKi 7.1–7.8) [375, 406] CCL26 (CCL26, Q9Y258) (pIC50 8.5) [1658] CXCL10 (CXCL10, P02778), CXCL11 (CXCL11, O14625), CXCL9 (CXCL9, Q07325)
Selective antagonists BX 471 (pKi 8.2–9) [1274], compound 2b-1 (pIC50 8.7) [1552], UCB35625 (pIC50 8) [1849], CP-481,715 (pKd 8) [708] GSK Compound 34 (pKi 7.6) banyu (I) (Inverse agonist) (pKi 8.5) [2247], SB328437 (pKi 8.4), BMS compound 87b (pKi 8.1) [2232]
Labelled ligands [125I]CCL7 (human) (Agonist) [140], [125I]CCL3 (human) (Agonist) [140, 720, 1870], [125I]CCL5 (human) (Agonist) [1870] [125I]CCL2 (human) (Agonist), [125I]CCL7 (human) (Agonist) [125I]CCL11 (human) (Antagonist) (pKd 8.3) [2247], [125I]CCL5 (human) (Agonist), [125I]CCL7 (human) (Agonist)
Nomenclature CCR4 CCR5 CCR6 CCR7 CCR8 CCR9 CCR10
HGNC, UniProt CCR4, P51679 CCR5, P51681 CCR6, P51684 CCR7, P32248 CCR8, P51685 CCR9, P51686 CCR10,, P46092
Endogenous agonists CCL22 (CCL22, O00626) [947], CCL17 (CCL17, Q92583) [947] CCL5 (CCL5, P13501) [87, 1547, 1833], CCL4 (CCL4, P13236) [1547, 1833], CCL8 (CCL8, P80075) [1833], CCL3 (CCL3, P10147)[1547, 1833, 2443], CCL11 (CCL11, P51671) [175], CCL2 (CCL2, P13500) [1547], CCL14 (CCL14, Q16627) [1547], CCL16 (CCL16, O15467) CCL20 (CCL20, P78556) [22, 86, 1730], beta-defensin 4A (DEFB4A DEFB4B, O15263) [2373] CCL21 (CCL21, O00585) [2399], CCL19 (CCL19, Q99731) [1640, 2398, 2399] CCL1 (CCL1, P22362) [441, 819, 948], CCL8 {Mouse} CCL25 (CCL25, O15444) CCL27 (CCL27, Q9Y4X3) [901], CCL28 (CCL28, Q9NRJ3)
Agonists vMIP-III R5-HIV-1 gp120 vMIP-I [441, 948]
Endogenous antagonists CCL7 (CCL7, P80098) (pKi 7.5) [1547]
Antagonists vicriviroc (pKi 9.1) [2043], ancriviroc (pKi 7.8–8.7) [1348, 1647, 2043]
Selective antagonists compound 8ic (pIC50 7.7) [2396] E913 (pIC50 8.7) [1349], aplaviroc (pKi 8.5) [1348], maraviroc (pIC50 8.1) [1547], TAK-779 (pKi 7.5) [1348], MRK-1 [1175] – Rat vMCC-I (pIC50 9.4) [441]
Selective allosteric modulators vercirnon (Antagonist) (pIC50 8.2) [2244]
Antibodies mogamulizumab (Inhibition) [58, 1962]
Labelled ligands [125I]CCL17 (human) (Agonist), [125I]CCL27 (human) (Agonist) [125I]CCL4 (human) (Agonist) [1547], [125I]CCL3 (human) (Agonist), [125I]CCL5 (human) (Agonist), [125I]CCL8 (human) (Agonist) [125I]CCL20 (human) (Agonist) [742] [125I]CCL19 (human) (Agonist), [125I]CCL21 (human) (Agonist) [989] [125I]CCL1 (human) (Agonist) [948, 1819] [125I]CCL25 (human) (Agonist)
Nomenclature CXCR1 CXCR2 CXCR3 CXCR4 CXCR5 CXCR6 CX3CR1
HGNC, UniProt CXCR1, P25024 CXCR2, P25025 CXCR3, P49682 CXCR4, P61073 CXCR5, P32302 CXCR6, O00574 CX3CR1, P49238
Endogenous agonists CXCL8 (CXCL8, P10145) [157, 783, 1239, 2316, 2336], CXCL6 (CXCL6, P80162) [2341] CXCL1 (CXCL1, P09341) [783, 1239, 2336], CXCL8 (CXCL8, P10145) [157, 783, 1239, 2316, 2336], CXCL7 (PPBP, P02775) [20], CXCL3 (CXCL3, P19876) [20], CXCL2 (CXCL2, P19875) [20], CXCL5 (CXCL5, P42830) [20], CXCL6 (CXCL6, P80162) [2341] CXCL11 (CXCL11, O14625) [845], CXCL10 (CXCL10, P02778) [845, 2285], CXCL9 (CXCL9, Q07325) [845, 2285] CXCL12α (CXCL12, P48061) [861, 1311], CXCL12β (CXCL12, P48061) [861] CXCL13 (CXCL13, O43927) [111] CXCL16 (CXCL16, Q9H2A7) [2309] CX3CL1 (CX3CL1, P78423) [664]
Agonists vCXCL1 [1334], HIV-1 matrix protein p17 [698] vCXCL1 [1334], HIV-1 matrix protein p17 [698]
Selective agonists ALX40-4C (Partial agonist) [2426], X4-HIV-1 gp120
Endogenous antagonists CCL11 (CCL11, P51671) (pKi 7.2) [2285], CCL7 (CCL7, P80098) (pKi 6.6) [2285]
Antagonists plerixafor (pKi 7) [2426]
Selective antagonists navarixin (pIC50 10.3) [90, 535], danirixin (pIC50 7.9) [1457], SB 225002 (pIC50 7.7) [2296], elubirixin (pIC50 7.7) [90], SX-517 (pIC50 7.2) [1347] T134 (pIC50 8.4) [2096], mavorixafor (pIC50 7.9) [1980], HIV-Tat
Allosteric modulators reparixin (Negative) (pIC50 9) [157] reparixin (Negative) (pIC50 6.4) [157]
Labelled ligands [125I]CXCL8 (human) (Agonist) [783, 1802] [125I]CXCL8 (human) (Agonist) [783, 1802], [125I]CXCL1 (human) (Agonist), [125I]CXCL5 (human) (Agonist), [125I]CXCL7 (human) (Agonist) [125I]CXCL10 (human) (Agonist), [125I]CXCL11 (human) (Agonist) [125I]CXCL12α (human) (Agonist) [491, 861] [125I]CXCL13 (mouse) (Agonist) [245] – Mouse [125I]CXCL16 (human) (Agonist) [125I]CX3CL1 (human) (Agonist)
Nomenclature XCR1 ACKR1 ACKR2 ACKR3 ACKR4 CCRL2
HGNC, UniProt XCR1, P46094 ACKR1, Q16570 ACKR2, O00590 ACKR3, P25106 ACKR4, Q9NPB9 CCRL2, O00421
Endogenous ligands CXCL5 (CXCL5, P42830), CXCL6 (CXCL6, P80162), CXCL8 (CXCL8, P10145), CXCL11 (CXCL11, O14625), CCL2 (CCL2, P13500), CCL5 (CCL5, P13501), CCL7 (CCL7, P80098), CCL11 (CCL11, P51671), CCL14 (CCL14, Q16627), CCL17 (CCL17, Q92583) chemerin C-terminal peptide, CCL19 (CCL19, Q99731) [109]
Endogenous agonists XCL1 (XCL1, P47992) [619], XCL2 (XCL2, Q9UBD3) [619] CCL2 (CCL2, P13500), CCL3 (CCL3, P10147), CCL4 (CCL4, P13236), CCL5 (CCL5, P13501), CCL7 (CCL7, P80098), CCL8 (CCL8, P80075), CCL11 (CCL11, P51671), CCL13 (CCL13, Q99616), CCL14 (CCL14, Q16627), CCL17 (CCL17, Q92583), CCL22 (CCL22, O00626) CXCL12α (CXCL12, P48061) [741, 2015], CXCL11 (CXCL11, O14625) CCL19 (CCL19, Q99731) [2276], CCL25 (CCL25, O15444) [2276], CCL21 (CCL21, O00585) [2276]
Comments XCL1 cannot be iodinated, but a secreted alkaline phophatase (SEAP)-XCL1 fusion peptide can be used as a probe at XCR1. ACKR1 is used by Plasmodium vivax and Plasmodium knowlsei for entering erythrocytes. Several lines of evidence have suggested that CGRP and adrenomedullin could be ligands for ACKR3; however, classical direct binding to the receptor has not yet been convincingly demonstrated [2074].

Comments

Specific chemokine receptors facilitate cell entry by microbes, such as ACKR1 for Plasmodium vivax, and CCR5 and CXCR4 for HIV-1. Virally encoded chemokine receptors are known (e.g. US28, a homologue of CCR1 from human cytomegalovirus and ORF74, which encodes a homolog of CXCR2 in Herpesvirus saimiri and gamma-Herpesvirus-68), but their role in viral life cycles is not established. Viruses can exploit or subvert the chemokine system by producing chemokine antagonists and scavengers. Three chemokine receptor antagonists have now been approved by the FDA: 1) the CCR5 antagonist maraviroc (Pfizer) for treatment of HIV/AIDS in patients with CCR5-using strains; and 2) the CXCR4 antagonist plerixafor (Sanofi) for hematopoietic stem cell mobilization with G-CSF (CSF3, P09919) in patients undergoing transplantation in the context of chemotherapy for Hodgkins’ Disease and multiple myeloma; and 3) the CCR4 blocking antibody Poteligeo (mogamulizumab-kpkc, Kyowa Kirin, Inc.) for mycosis fungoides or Sezary syndrome.

Further reading on Chemokine receptors

Bachelerie F et al. (2015) An atypical addition to the chemokine receptor nomenclature: IUPHAR Review 15. Br. J. Pharmacol. 172: 3945-9 [PMID:25958743]

Murphy PM et al. (2000) International Union of Pharmacology. XXII. Nomenclature for chemokine receptors. Pharmacol. Rev. 52: 145-176 [PMID:10699158]

Koelink PJ et al. (2012) Targeting chemokine receptors in chronic inflammatory diseases: an extensive review. Pharmacol. Ther. 133: 1-18 [PMID:21839114]

Scholten DJ et al. (2012) Pharmacological modulation of chemokine receptor function. Br. J. Pharmacol. 165: 1617-43 [PMID:21699506]

Murphy PM. (2002) International Union of Pharmacology. XXX. Update on chemokine receptor nomenclature. Pharmacol. Rev. 54: 227-9 [PMID:12037138]

Cholecystokinin receptors

Overview

Cholecystokinin receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on CCK receptors [1598) are activated by the endogenous peptides cholecystokinin-8 (CCK-8 (CCK, P06307)), CCK-33 (CCK, P06307), CCK-58 (CCK, P06307) and gastrin (gastrin-17 (GAST, P01350)). There are only two distinct subtypes of CCK receptors, CCK1 and CCK2 receptors [1139, 2263], with some alternatively spliced forms most often identified in neoplastic cells. The CCK receptor subtypes are distinguished by their peptide selectivity, with the CCK1 receptor requiring the carboxyl-terminal heptapeptide-amide that includes a sulfated tyrosine for high affinity and potency, while the CCK2 receptor requires only the carboxyl-terminal tetrapeptide shared by each CCK and gastrin peptides. These receptors have characteristic and distinct distributions, with both present in both the central nervous system and peripheral tissues.

Nomenclature CCK1 receptor CCK2 receptor
HGNC, UniProt CCKAR, P32238 CCKBR, P32239
Potency order of endogenous ligands CCK-8 (CCK, P06307), CCK-58 (CCK, P06307), CCK-39 (CCK), CCK-33 (CCK, P06307) gastrin-17 (GAST, P01350), desulfated cholecystokinin-8 > CCK-4 (CCK, P06307) CCK-8 (CCK, P06307), CCK-39 (CCK), CCK-33 (CCK, P06307), CCK-58 (CCK, P06307) ≥ gastrin-17 (GAST, P01350), desulfated cholecystokinin-8, CCK-4 (CCK, P06307)
Endogenous agonists CCK-33 (CCK, P06307), CCK-39 (CCK), CCK-58 (CCK, P06307), CCK-8 (CCK, P06307) desulfated cholecystokinin-8 [1242], gastrin-17 (GAST, P01350) [931] – Mouse, CCK-4 (CCK, P06307) [957], desulfated gastrin-14 (GAST, P01350), desulfated gastrin-17 (GAST, P01350), desulfated gastrin-34 (GAST, P01350), desulfated gastrin-71 (GAST, P01350), gastrin-14 (GAST, P01350), gastrin-34 (GAST, P01350), gastrin-71 (GAST, P01350)
Selective agonists A-71623 [74] – Rat, JMV180 [1068], GW-5823 [851] RB-400 [138] – Rat, PBC-264 [974] – Rat
Antagonists lintitript (pIC50 8.3) [733]
Selective antagonists devazepide (pIC50 9.7) [931] – Rat, T-0632 (pIC50 9.6) [2103] – Rat, PD-140548 (pIC50 8.6) [1977] – Rat, lorglumide (pIC50 6.7–8.2) [931, 963] – Rat YF-476 (pIC50 9.7) [218, 2094], GV150013 (pIC50 9.4) [2180], L-740093 (pIC50 9.2) [1590], YM-022 (pIC50 9.2) [1590], JNJ-26070109 (pIC50 8.5) [1510], L-365260 (pIC50 8.4) [1242], RP73870 (pIC50 8) [1291] – Rat, LY262691 (pIC50 7.5) [1773] – Rat
Labelled ligands [3H]devazepide (Antagonist) (pKd 9.7) [338], [125I]DTyr-Gly-[(Nle28,31)CCK-26-33 (Agonist) [1731] [3H]PD140376 (Antagonist) (pKi 9.7–10) [935] – Guinea pig, [125I]PD142308 (Antagonist) (pKd 9.6) [905] – Guinea pig, [125I]DTyr-Gly-[(Nle28,31)CCK-26-33 (Agonist) [1731], [125I]gastrin (Agonist), [3H]gastrin (Agonist), [3H]L365260 (Antagonist) (pKd 8.2–8.5) [1590], [125I]-BDZ2 (Antagonist) (pKi 8.4) [27]

Comments

While a cancer-specific CCK receptor has been postulated to exist, which also might be responsive to incompletely processed forms of CCK (Gly-extended forms), this has never been isolated. An alternatively spliced form of the CCK2 receptor in which intron 4 is retained, adding 69 amino acids to the intracellular loop 3 (ICL3) region, has been described to be present particularly in certain neoplasms where mRNA mis-splicing has been commonly observed [1995], but it is not clear that this receptor splice form plays a special role in carcinogenesis. Another alternative splicing event for the CCK2 receptor was reported [2012], with alternative donor sites in exon 4 resulting in long (452 amino acids) and short (447 amino acids) forms of the receptor differing by five residues in ICL3, however, no clear functional differences have been observed.

Further reading on Cholecystokinin receptors

Ballaz S. (2017) The unappreciated roles of the cholecystokinin receptor CCK(1) in brain functioning. Rev Neurosci 28: 573-585 [PMID:28343167]

Dockray GJ. (2009) Cholecystokinin and gut-brain signalling. Regul. Pept. 155: 6-10 [PMID:19345244]

Cawston EE et al. (2010) Therapeutic potential for novel drugs targeting the type 1 cholecystokinin receptor. Br. J. Pharmacol. 159: 1009-21 [PMID:19922535]

Dufresne M et al. (2006) Cholecystokinin and gastrin receptors. Physiol. Rev. 86: 805-47 [PMID:16816139]

Class Frizzled GPCRs

Overview

Receptors of the Class Frizzled (FZD, nomenclature as agreed by the NC-IUPHAR subcommittee on the Class Frizzled GPCRs [1902]), are GPCRs originally identified in Drosophila [332], which are highly conserved across species. While SMO shows structural resemblance to the 10 FZDs, it is functionally separated as it mediates effects in the Hedgehog signaling pathway [1902]. FZDs are activated by WNTs, which are cysteine-rich lipoglycoproteins withfundamentalfunctions inontogeny and tissue homeostasis. FZD signalling was initially divided into two pathways, being either dependent on the accumulation of the transcription regulator β-catenin (CTNNB1, P35222) or being β-catenin-independent (often referred to as canonical vs. non-canonical WNT/FZD signalling, respectively). WNT stimulation of FZDs can, in cooperation with the low density lipoprotein receptors LRP5 (O75197) and LRP6 (O75581), lead to the inhibition of a constitutively active destruction complex, which results in the accumulation of β-catenin and subsequently its translocation to the nucleus. β-Catenin, in turn, modifies gene transcription by interacting with TCF/LEF transcription factors. βCatenin-independent FZD signalling is far more complex with regard to the diversity of the activated pathways. WNT/FZD signalling can lead to the activation of heterotrimeric G proteins [496, 1694, 1903], the elevation of intracellular calcium [1989], activation of cGMP-specific PDE6 [21] and elevation of cAMP as well as RAC-1, JNK, Rho and Rho kinase signalling [802]. Novel resonance energy transfer-based tools have allowed the study of the GPCR-like nature of FZDs in greater detail. Upon ligand stimulation, FZDs undergo conformational changes and signal via heterotrimeric G proteins [2332, 2333]. Furthermore, the phosphoprotein Dishevelled constitutes a key player in WNT/FZD signalling. Importantly, FZDs exist in at least two distinct conformational states that regulate the pathway selection [2333]. As with other GPCRs, members of the Frizzled family are functionally dependent on the arrestin scaffolding protein for internalization [354], as well as for β-catenin-dependent [262] and -independent [263, 1084] signalling. The pattern of cell signalling is complicated by the presence of additional ligands, which can enhance or inhibit FZD signalling (secreted Frizzled-related proteins (sFRP), Wnt-inhibitory factor (WIF1, Q9Y5W5) (WIF), sclerostin (SOST, Q9BQB4) or Dickkopf (DKK)), as well as modulatory (co)-receptors with Ryk, ROR1, ROR2 and Kremen, which may also function as independent signalling proteins.

Nomenclature FZD1 FZD2 FZD3 FZD4 FZD5
HGNC, UniProt FZD1, Q9UP38 FZD2, Q14332 FZD3, Q9NPG1 FZD4, Q9ULV1 FZD5, Q13467
Allosteric modulators FzM1.8 (Negative) (pIC50 5.5–7.8) [679], FzM1.8 (Positive) (pEC50 6.4) [1799], FzM1 (Negative) (pIC50 6.2) [679, 1799]
Antibodies vantictumab (Antagonist) (pIC50 ∼9.1) [771] vantictumab (Antagonist) (pIC50 ∼9) [771] vantictumab (Antagonist) (pIC50 ∼9) [771]
Comments IgG-2919 and IgG-2921 are FZD5 antibodies that have exhibited antitumour activities in vitro and in vivo (inhibiting the growth of RNF43-mutant pancreatic ductal adenocarcinoma cells/xenograft tumours), by blocking autocrine Wnt-β-catenin signalling in these mutant, FZD5-dependent cells [2029].
Nomenclature FZD6 FZD7 FZD8 FZD9 FZD10
HGNC, UniProt FZD6, O60353 FZD7, O75084 FZD8, Q9H461 FZD9, O00144 FZD10, Q9ULW2
Selective antagonists Fz7-21 (pIC50 7) [1589]
Antibodies vantictumab (Antagonist) (pIC50 ∼9) [771] vantictumab (Antagonist) (pIC50 ∼8) [771]
Comments FZD8-Fc/OMP-54F28 is a FZD8 antagonist [477]. Radio-labelled murine monoclonal antibody MAb 92-13 has been used to demonstrate the therapeutic potential of targeting FZD10-positive tumours [639].
Nomenclature SMO
HGNC, UniProt SMO, Q99835
Agonists SMO agonist (SAG) [350] – Mouse, purmorphamine [1978]
Antagonists MRT-92 (pKd 9.5) [890], SANT-1 (pKi 7.7) [350] – Mouse, cyclopamine-KAAD (pIC50 7.7) [2080] – Mouse, cyclopamine (pIC50 ∼7) [2162] – Mouse
Selective antagonists vismodegib (pKi 7.8) [2252]
Allosteric modulators GSA-10 (Positive) (pEC50 5.9) [726]
Comments SANT-3 and SANT-4 are SMO antagonists [350].

Comments

There is limited knowledge about WNT/FZD specificity and which molecular entities determine the signalling outcome of a specific WNT/FZD pair. Understanding of theFZD and SMO coupling to G proteins is incomplete, but progress have been made [72, 496, 1083, 1374, 1808, 1945, 2229, 2332]. There is also a scarcity of information on basic pharmacological characteristics of FZDs, such as binding constants, ligand specificity or concentration-response relationships [1081]. Development of pharmacological tools for SMO has been faciliated by successful crystalization of several SMO structures [278, 924, 2250, 2251, 2279, 2427]. The recently solved FZD4 in apo state has provided first insight into FZD transmembranous organization [2380].

Ligands associated with FZD signalling

WNTs: Wnt-1 (WNT1, P04628), Wnt-2 (WNT2, P09544) (also known as Int-1-related protein), Wnt-2b (WNT2B, Q93097) (also known as WNT-13), Wnt-3 (WNT3, P56703), Wnt-3a (WNT3A, P56704), Wnt-4 (WNT4, P56705), Wnt-5a (WNT5A, P41221) (pEC50 7.7-8.9 [2332]), Wnt-5b (WNT5B, Q9H1J7), Wnt-6 (WNT6, Q9Y6F9), Wnt-7a (WNT7A, O00755), Wnt-7b (WNT7B, P56706), Wnt-8a (WNT8A, Q9H1J5), Wnt-8b (WNT8B, Q93098), Wnt-9a (WNT9A, O14904) (also known as WNT-14), Wnt-9b (WNT9B, O14905) (also known as WNT-15 or WNT14b), Wnt-10a(WNT10A, Q9GZT5), Wnt-10b (WNT10B, O00744) (also known as WNT-12), Wnt-11 (WNT11, O96014) and Wnt-16 (WNT16, Q9UBV4).

Extracellular proteins that interact with FZDs: norrin (NDP, Q00604), R-spondin-4 (RSPO4, Q2I0M5), sFRP-1 (SFRP1, Q8N474), sFRP-2 (SFRP2, Q96HF1), sFRP-3 (FRZB,Q92765), sFRP-4 (SFRP4, Q6FHJ7), sFRP-5 (SFRP5, Q6FHJ7).

Extracellular proteins that interact with WNTs or LRPs: Dickkopf 1 (DKK1, O94907), WIF1 (Q9Y5W5), sclerostin (SOST, Q9BQB4), kremen 1 (KREMEN1, Q96MU8) and kremen 2 (KREMEN2, Q8NCW0)

Small exogenous ligands: Foxy-5 [2075], Box-5 [988], UM206 [1189], and XWnt8 (P28026) also known as mini-Wnt8.

Ligands associated with SMO signalling: cholesterol, oxysterols [278, 1325, 1761].

Further reading on Class Frizzled GPCRs

Angers S et al. (2009) Proximal events in Wnt signal transduction. Nat. Rev. Mol. Cell Biol. 10: [PMID:22935904]

van Amerongen R. (2012) Alternative Wnt pathways and receptors. Cold Spring Harb Perspect Biol 4: 468-77 [PMID:19536106]

Schulte G.(2015)Frizzleds and WNT/β-cateninsignaling–The black boxof ligand-receptor selectivity, 113-39 [PMID:26969975]

Wang Y et al. (2016) Frizzled Receptors in Development and Disease. Curr. Top. Dev. Biol. 117: complex stoichiometry and activation kinetics. Eur. J. Pharmacol. 763: 191-5 [PMID:26003275]

Schulte G et al. (2018) Frizzleds as GPCRs - More Conventional Than We Thought! Trends Pharmacol. Sci. 39: 828-842 [PMID:30049420]

Complement peptide receptors

Overview

Complement peptide receptors (nomenclature as agreed by the NC-IUPHAR subcommittee on Complement peptide receptors [1114]) are activated by the endogenous 75 amino-acid anaphylatoxin polypeptides C3a (C3, P01024) and C5a (C5, P01031), generated upon stimulation of the complement cascade. C3a and C5a exert their functions through binding to their receptors (C3aR and C5aR), causing cell activation and triggering cellular degranulation that contributes to the local inflammation.

Nomenclature C3a receptor C5a1 receptor C5a2 receptor
HGNC, UniProt C3AR1, Q16581 C5AR1, P21730 C5AR2, Q9P296
Potency order of endogenous ligands C3a (C3, P01024) > C5a (C5, P01031) [45] C5a (C5, P01031), C5a des-Arg (C5) > C3a (C3, P01024) [45]
Endogenous agonists ribosomal protein S19 (RPS19, P39019) [2363]
Agonists compound 17 [1786], compound 21 [1785], casoxin C [2082, 2402], albutensin A 2086, 2402], oryzatensin [1003, 2083, 2402] NDT9513727 (Inverse agonist) [244], N-methyl-Phe-Lys-Pro-D-Cha-Cha-D-Arg-CO2H [1054, 1136], lactomedin 1 [2276, 2402]
Selective agonists P59 (Biased agonist) [434], P32 (Biased agonist) [434]
Antagonists SB290157 (pIC50 7.6) [44], compound 4 (pIC50 5.9) [1785] avacopan (pIC50 9.7) [134], W54011 (pKi 8.7) [2056], DF2593A (pIC50 8.3) [1499], AcPhe-Orn-Pro-D-Cha-Trp-Arg (pIC50 7.9) [2323], N-methyl-Phe-Lys-Pro-D-Cha-Trp-D-Arg-CO2H (pIC50 7.2) [1136]
Labelled ligands [125I]C3a (human) (Agonist) [342] [125I]C5a (human) (Agonist) [929] [125I]C5a (human) (Agonist)
Comments C3a-C3aR signalling plays a crucial role in inhibiting neural progenitor cell proliferation during neurodevelopment, playing a critical role in the normal development of the mammalian brain [426].

Comments

SB290157 has also been reported to have agonist properties at the C3a receptor [1396]. The putative chemoattractant receptor termed C5a2 (also known as GPR77, C5L2) binds [125I]C5a with no clear signalling function, but has a putative role opposing inflammatory responses [291, 655, 673]. Binding to this site may be displaced with the rank order C5a des-Arg (C5)> C5a (C5, P01031)[291, 1631] while there is controversy over the ability of C3a (C3, P01024) and C3a des Arg (C3, P01024) to compete [902, 1029, 1030, 1631]. C5a2 appears to lack G protein signalling and has been termed a decoy receptor [1910]. However, C5a2 does recruit arrestin after ligand binding, which might provide a signaling pathway for this receptor [103, 2192], and forms heteromers with C5a1. C5a, but not C5a-des Arg, induces upregulation of heteromer formation between complement C5a receptors C5a1 and C5a2 [433]. There are also reports of pro-inflammatory activity of C5a2, mediated by HMGB1, but the signaling pathway that underlies this is currently unclear (reviewed in [1271]). More recently, work in T cells has shown that C5a1 and C5a2 act in opposition to each other and that altering the equilibrium between the two receptors, by differential expression or production of C5a-des Arg (which favours C5a2), can affect the final cellular response [61].

Further reading on Complement peptide receptors

Arbore G et al. (2016) A novel "complement-metabolism-inflammasome axis" as a key regulator of immune cell effector function. Eur. J. Immunol. 46: 1563-73 [PMID:27184294]

Coulthard LG et al. (2018) Complement C3a receptor modulates embryonic neural progenitor cell proliferation and cognitive performance. Mol. Immunol. 101: 176-181 [PMID:30449309]

Laumonnier Y et al. (2017) Novel insights into the expression pattern of anaphylatoxin receptors in mice and men. Mol. Immunol. 89: 44-58 [PMID:28600003]

Li R et al. (2013) C5L2: a controversial receptor of complement anaphylatoxin, C5a. FASEB J. 27: 855-64 [PMID:23239822]

Monk PN et al. (2007) Function, structure and therapeutic potential of complement C5a receptors. Br. J. Pharmacol. 152: 429-48 [PMID:17603557]

Reichhardt MP et al. (2018) Intracellular complement activation-An alarm raising mechanism? Semin. Immunol. 38: 54-62 [PMID:29631809]

Corticotropin-releasing factor receptors

Overview

Corticotropin-releasing factor (CRF, nomenclature as agreed by the NC-IUPHAR subcommittee on Corticotropin-releasing Factor Receptors [824]) receptors are activated by the endogenous peptides corticotrophin-releasing hormone (CRH, P06850), a 41 aminoacid peptide, urocortin 1 (UCN, P55089), 40 amino-acids, urocortin 2 (UCN2, Q96RP3), 38 amino-acids and urocortin 3 (UCN3, Q969E3), 38 amino-acids. CRF1 and CRF2 receptors are activated non-selectively by CRH and UCN. CRF2 receptors are selectively activated by UCN2 and UCN3. Binding to CRF receptors can be conducted using radioligands [125I]Tyr0-CRF or [125I]Tyr0-sauvagine with Kd values of 0.1-0.4 nM. CRF1 and CRF2 receptors are non-selectively antagonized by α-helical CRF, D-Phe-CRF-(12-41) and astressin. CRF1 receptors are selectively antagonized by small molecules NBI27914, R121919, antalarmin, CP 154,526, CP 376,395. CRF2 receptors are selectively antagonized by antisauvagine and astressin 2B.

Nomenclature CRF1 receptor CRF2 receptor
HGNC, UniProt CRHR1, P34998 CRHR2, Q13324
Endogenous agonists urocortin 1 (UCN, P55089) [451, 453, 508], corticotrophin-releasing hormone (CRH, P06850) [353, 450, 453, 508, 1648, 2212] urocortin 2 (UCN2, Q96RP3) [451], urocortin 3 (UCN3, Q969E3)[451]
Antagonists SSR125543A (pKi 8.7) [766], astressin (pKi 8.7) [1812] astressin (pIC50 9.2) [1810]
Selective antagonists CP 154,526 (pIC50 9.3–10.4) [1328] – Rat, DMP696 (pKi 8.3–9) [835], NBI27914 (pKi 8.3–9) [346], R121919 (pKi 8.3–9) [2442], antalarmin (pKi 8.3–9) [2278], CP 376,395 (pIC50 8.3) [355] – Rat, CRA1000 (pIC50 6.4–7.1) [330] antisauvagine (pKd 8.8–9.6) [453], K41498 (pKi 9.2) [1211], astressin 2B (pIC50 8.9) [1810], K31440 (pKi 8.7–8.8) [1846]

Comments

A CRF binding protein has been identified (CRHBP, P24387) to which both corticotrophin-releasing hormone (CRH, P06850) and urocortin 1 (UCN, P55089) bind with high affinities, which has been suggested to bind and inactivate circulating corticotrophin-releasing hormone (CRH, P06850) [1686].

Further reading on Corticotropin-releasing factor receptors

Deussing JM et al. (2018) The Corticotropin-Releasing Factor Family: Physiology of the Stress Response. Physiol. Rev. 98: 2225-2286 [PMID:30109816]

Hauger RL et al. (2003) International Union of Pharmacology. XXXVI. Current status of the nomenclature for receptors for corticotropin-releasing factor and their ligands. Pharmacol Rev. 55: 21-26 [PMID:12615952]

Grammatopoulos DK. (2012) Insights into mechanisms of corticotropin-releasing hormone receptor signal transduction. Br. J. Pharmacol. 166: 85-97 [PMID:21883143]

Liapakis G et al. (2011) Members of CRF family and their receptors: from past to future. Curr. Med. Chem. 18: 2583-600 [PMID:21568890]

Slater PG et al. (2016) Corticotropin-Releasing Factor Receptors and Their Interacting Proteins: Functional Consequences. Mol. Pharmacol. 90: 627-632 [PMID:27612874]

Zelenay V et al. (2017) Structures of the First Extracellular Domain of CRF Receptors. Curr Mol Pharmacol 10: 318-324 [PMID:28103782]

Dopamine receptors

Overview

Dopamine receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on Dopamine Receptors [1906]) are commonly divided into D1-like (D1 and D5) and D2-like (D2, D3 and D4) families, where the endogenous agonist is dopamine.

Nomenclature D1 receptor D2 receptor
HGNC, UniProt DRD1, P21728 DRD2, P14416
Sub/family-selective labelled ligands [125I]SCH23982 (Antagonist) (pKd 9.5) [478], [3H]SCH-23390 (Antagonist) (pKd 9.5) [2435] [3H]spiperone (Antagonist) (pKd 10.2) [266, 888, 2433] – Rat
Endogenous agonists dopamine [2060, 2132] dopamine [272, 628, 1876]
Agonists fenoldopam [2132] rotigotine [497], cabergoline (Partial agonist) [1451], aripiprazole (Partial agonist) [2410], bromocriptine [628, 1451, 1876], MLS1547 (Biased agonist) [627], ropinirole [843], apomorphine (Partial agonist) [272, 628, 1451, 1876, 2006], pramipexole [1446, 1876], benzquinamide [744]
Sub/family-selective agonists A68930 [1569], SKF-38393 (Partial agonist) [2060, 2132] quinpirole [272, 1446, 1665, 2006, 2008, 2196]
Selective agonists SKF-83959 (Biased agonist) [413], A77636 [1844], SKF-81297 [50] – Rat sumanirole [1415]
Antagonists flupentixol (pKi 7–8.4) [2060, 2132] blonanserin (pKi 9.9) [1611], pipotiazine (pKi 9.7) [2007], perphenazine (pKi 8.9–9.6) [1156, 1920], risperidone (pKi 9.4) [70], perospirone (pKi 9.2) [1919], trifluoperazine (pKi 8.9–9) [1156, 1920], quetiapine (pKi 7.2) [70]
Sub/family-selective antagonists SCH-23390 (pKi 7.4–9.5) [2060, 2132], SKF-83566 (pKi 9.5) [2060], ecopipam (pKi 8.3) [2133] haloperidol (pKi 7.4–8.8) [628, 1341, 1446, 2006, 2133]
Selective antagonists L-741,626 (pKi 7.9–8.5) [755, 1171], domperidone (pKi 7.9–8.4) [628, 2006], raclopride (pKi 8) [1453], ML321 (pKi 7) [2347, 2348]
Labelled ligands [3H]raclopride (Antagonist) (pKd 8.9) [1184] – Rat
Nomenclature D3 receptor D4 receptor D5 receptor
HGNC, UniProt DRD3, P35462 DRD4, P21917 DRD5, P21918
Sub/family-selective labelled ligands [3H]spiperone (Antagonist) (pKd 9.5) [866, 2196] [3H]SCH-23390 (Antagonist) (pKd 9.2) [1797]
Endogenous agonists dopamine [272, 628, 1876, 2008] dopamine [2196] dopamine [2060]
Agonists pramipexole [1446, 1876], bromocriptine (Partial agonist) [628, 1451, 1876], ropinirole [843], apomorphine (Partial agonist) [272, 628, 1451, 1876, 2006] apomorphine (Partial agonist) [1451]
Sub/family-selective agonists quinpirole [272, 1446, 1453, 1665, 1876, 2006, 2008, 2196] quinpirole [1451, 1665, 2196] A68930 [1569]
Selective agonists PD 128907 [1745, 1876] PD168,077 (Partial agonist) [1141] – Rat, A412997 [1491] – Rat, A412997 [1491]
Antagonists perospirone (pKi 9.6) [2006], sertindole (pKi 8–8.8) [70, 1901, 1920], prochlorperazine (pKi 8.4) [79], (-)-sulpiride (pKi 6.7–7.7) [628, 2006, 2102], loxapine (pKi 7.7) [1920], domperidone (pKi 7.1–7.6) [628, 2006], promazine (pKi 6.8) [273] perospirone (pKi 10.1) [1921], sertindole (pKi 7.8–9.1) [273, 1920, 1920, 1921], sonepiprazole (pKi 8.9) [1892], loxapine (pKi 8.1) [1920]
Sub/family-selective antagonists haloperidol (pKi 7.5–8.6) [628, 1939, 2006, 2133] haloperidol (pKi 8.7–8.8) [1191, 1939, 2133] SCH-23390 (pKi 7.5–9.5) [2060], SKF-83566 (pKi 9.4) [2060], ecopipam (pKi 8.3) [2060]
Selective antagonists S33084 (pKi 9.6) [1450], nafadotride (pKi 9.5) [1877], PG01037 (pKi 9.2) [756], NGB 2904 (pKi 8.8) [2343], SB 277011-A (pKi 8) [1783], (+)-S-14297 (pKi 6.9–7.9) [1448, 1453] L745870 (pKi 9.4) [1171], A-381393 (pKi 8.8) [1543], L741742 (pKi 8.5) [1831], ML398 (pKi 7.4) [154]
Selective allosteric modulators SB269652 (Negative) (pKi ∼9) [642]
Labelled ligands [3H]spiperone (Antagonist) (pKd 9.9) [888, 2433] – Rat, [3H]7-OH-DPAT (Agonist) [1798], [3H]PD128907 (Agonist) [29] [125I]L750667 (Antagonist) (pKd 9.8) [1665], [3H]NGD941 (Antagonist) (pKd 8.3) [1736] [125I]SCH23982 (Antagonist) (pKd 9.1)

Comments

The selectivity of many of these agents is less than two orders of magnitude. [3H]raclopride exhibits similar high affinity for D2 and D3 receptors (low affinity for D4), but has been used to label D2 receptors in the presence of a D3-selective antagonist. [3H]7-OH-DPAT has similar affinity for D2 and D3 receptors, but labels only D3 receptors in the absence of divalent cations. The pharmacological profile of the D5 receptor is similar to, yet distinct from, that of the D1 receptor. The splice variants of the D2 receptor are commonly termed D2S and D2L (short and long). The DRD4 gene encoding the D4 receptor is highly polymorphic in humans, with allelic variations of the protein from amino acid 387 to 515.

Further reading on Dopamine receptors

Beaulieu JM et al. (2015) Dopamine receptors - IUPHAR Review 13. Br. J. Pharmacol. 172: 1-23 [PMID:25671228]

Beaulieu JM et al. (2011) The physiology, signaling, and pharmacology of dopamine receptors. Pharmacol. Rev. 63: 182-217 [PMID:21303898]

Cumming P. (2011) Absolute abundances and affinity states of dopamine receptors in mammalian brain: A review. Synapse 65: 892-909 [PMID:21308799]

Maggio R et al. (2010) Dopamine D2-D3 receptor heteromers: pharmacological properties and therapeutic significance. Curr Opin Pharmacol 10: 100-7 [PMID:19896900]

Ptácek R et al. (2011) Dopamine D4 receptor gene DRD4 and its association with psychiatric disorders. Med. Sci. Monit. 17: RA215-20 [PMID:21873960]

Schwartz J-C et al. (1998) Dopamine Receptors. In The IUPHAR Compendium of Receptor Characterization and Classification Edited by Girdlestone D: IUPHAR Media: 141-151

Undieh AS. (2010) Pharmacology of signaling induced by dopamine D(1)-like receptor activation. Pharmacol. Ther. 128: 37-60 [PMID:20547182]

Endothelin receptors

Overview

Endothelin receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on Endothelin Receptors [454]) are activated by the endogenous 21 amino-acid peptides endothelins 1-3 (endothelin-1 (EDN1, P05305), endothelin-2 (EDN2, P20800) and endothelin-3 (EDN3, P14138)).

Nomenclature ETA receptor ETB receptor
HGNC, UniProt EDNRA, P25101 EDNRB, P24530
Potency order of endogenous ligands endothelin-1 (EDN1, P05305) = endothelin-2 (EDN2, P20800) > endothelin-3 (EDN3, P14138) [1353] endothelin-1 (EDN1, P05305) = endothelin-2 (EDN2, P20800), endothelin-3 (EDN3, P14138) [1854]
Selective agonists sarafotoxin S6c [1163, 1838], BQ 3020 [1793], [Ala1,3,11,15]ET-1 [1471], IRL 1620 [2268]
Antagonists SB209670 (pKB 9.4) [553] – Rat, TAK 044 (pA2 8.4) [2271] – Rat, bosentan (pA2 7.2) [403] – Rat SB209670 (pKB 9.4) [553] – Rat, TAK 044 (pA2 8.4) [2271] – Rat, bosentan (pKi 7.1) [1527]
Selective antagonists macitentan (pIC50 9.3) [192], sitaxsentan (pA2 8) [2334], FR139317 (Inverse agonist) (pIC50 7.3–7.9) [1353], BQ123 (pA2 6.9–7.4) [1353], ambrisentan (pA2 7.1) [193] K-8794 (pIC50 8.2) [1951], A192621 (pKd 8.1) [2226], BQ788 (pKd 7.9–8) [1838], IRL 2500 (pKd 7.2) [1838], Ro 46-8443 (pIC50 7.2) [232]
Labelled ligands [125I]PD164333 (Antagonist) (pKd 9.6–9.8) [457], [3H]S0139 (Antagonist) (pKd 9.2), [125I]PD151242 (Antagonist) (pKd 9–9.1) [458], [3H]BQ123 (Antagonist) (pKd 8.5) [944] [125I]IRL1620 (Agonist) [1544], [125I]BQ3020 (Agonist) [810, 1471, 1693], [125I][Ala1,3,11,15]ET-1 (Agonist) [1471]

Comments

Splice variants of the ETA receptor have been identified in rat pituitary cells; one of these, ETAR-C13, appeared to show loss of function with comparable plasma membrane expression to wild type receptor [822]. Subtypes of the ETB receptor have been proposed, although gene disruption studies in mice suggest that only a single gene product exists [1465]. Crystal structures of the ETB receptor bound to the antagonist bosentan and ETB selective analogue K-8794 [1951] and selective ETB agonists endothelin-3 (EDN3, P14138) and IRL 1620 [1950] have been reported.

Further reading on Endothelin receptors

Clozel M et al. (2013) Endothelin receptor antagonists. Handb Exp Pharmacol 218: 199-227 [PMID:24092342]

Davenport AP. (2002) International Union of Pharmacology. XXIX. Update on endothelin receptor nomenclature. Pharmacol. Rev. 54: 219-26 [PMID:12037137]

Davenport AP et al. (2016) Endothelin. Pharmacol. Rev. 68: 357-418 [PMID:26956245]

Davenport AP et al. (2018) New drugs and emerging therapeutic targets in the endothelin signaling pathway and prospects for personalized precision medicine. Physiol Res 67: S37-S54 [PMID:29947527]

Maguire JJ et al. (2014) Endothelin@25 - new agonists, antagonists, inhibitors and emerging research frontiers: IUPHAR Review 12. Br. J. Pharmacol. 171: 5555-72 [PMID:25131455]

G protein-coupled estrogen receptor

Overview

The G protein-coupled estrogen receptor (GPER, nomenclature as agreed by the NC-IUPHAR Subcommittee on the G protein-coupled estrogen receptor [1740]) was identified following observations of estrogen-evoked cyclic AMP signalling in breast cancer cells [71], which mirrored the differential expression of an orphan 7-transmembrane receptor GPR30 [304]. There are observations of both cell-surface and intracellular expression of the GPER receptor [1789, 2123]. Selective agonist/ antagonists for GPER have been characterized [1740]. Antagonists of the nuclear estrogen receptor, such as fulvestrant [596], tamoxifen [1789, 2123] and raloxifene [1700], as well as the flavonoid ’phytoestrogens’ genistein and quercetin [1352], are agonists of GPER. A complete review of GPER pharmacology has been recently published [1740]. The roles of GPER in physiological systems throughout the body (cardiovascular, metabolic, endocrine, immune, reproductive) and in cancer have also been reviewed [595, 1203, 1437, 1740, 1741].

Nomenclature GPER
HGNC, UniProt GPER1, Q99527
Agonists fulvestrant [2123], raloxifene [1700], 4-hydroxytamoxifen [1789]
Selective agonists G-1 [195]
Selective antagonists G36 (pIC50 6.8–6.9) [485], G15 (pIC50 6.7) [484]
Labelled ligands [3H]17β-estradiol (Agonist) [2123]

Comments

Antagonists at the nuclear estrogen receptor, such as fulvestrant, tamoxifen [596] and raloxifene [1700], as well as the flavonoid ‘phytoestrogens’ genistein and quercetin [1352], are agonists at GPER receptors. A complete review of GPER pharmacology has been recently published [1740].

Further reading on G protein-coupled estrogen receptor

Barton M et al. (2018) Twenty years of the G protein-coupled estrogen receptor GPER: Historical and personal perspectives. J. Steroid Biochem. Mol. Biol. 176: 4-15 [PMID:28347854]

Gaudet HM et al. (2015) The G-protein coupled estrogen receptor, GPER: The inside and inside-out story. Mol. Cell. Endocrinol. 418 Pt 3: 207-19 [PMID:26190834]

Prossnitz ER et al. (2015) International Union of Basic and Clinical Pharmacology. XCVII. G Protein-Coupled Estrogen Receptor and Its Pharmacologic Modulators. Pharmacol. Rev. 67: 505-40 [PMID:26023144]

Prossnitz ER et al. (2015) What have we learned about GPER function in physiology and disease from knockout mice? J. Steroid Biochem. Mol. Biol. 153: 114-26 [PMID:26189910]

Formylpeptide receptors

Overview

The formylpeptide receptors (nomenclature agreed by the NC-IUPHAR Subcommittee on the formylpeptide receptor family [2387]) respond to exogenous ligands such as the bacterial product fMet-Leu-Phe (fMLP) and endogenous ligands such as annexin I (ANXA1, P04083), cathepsin G (CTSG, P08311), amyloid β42, serum amyloid A and spinorphin, derived from β-haemoglobin (HBB, P68871).

Nomenclature FPR1 FPR2/ALX FPR3
HGNC, UniProt FPR1, P21462 FPR2, P25090 FPR3, P25089
Potency order of endogenous ligands fMet-Leu-Phe > cathepsin G (CTSG, P08311) > annexin I (ANXA1, P04083) [1224, 2058] LXA4 = aspirin triggered lipoxin A4 = ATLa2 = resolvin D1 > LTC4 = LTD4 15-deoxy-LXA4 fMet-Leu-Phe [401, 600, 602, 750, 2086]
Endogenous agonists LXA4 [1153], resolvin D1 [1153], aspirin-triggered resolvin D1 [1152], aspirin triggered lipoxin A4 F2L (HEBP1, Q9NRV9) [1447]
Agonists fMet-Leu-Phe [630, 1963]
Selective agonists ATLa2 [765]
Endogenous antagonists spinorphin (pIC50 4.3) [1275, 1526]
Antagonists t-Boc-FLFLF (pKi 6–6.5) [2288]
Selective antagonists cyclosporin H (pKi 6.1–7.1) [2288, 2370] WRWWWW (pIC50 6.6) [92], t-Boc-FLFLF (pIC50 4.3–6) [629, 2030, 2245]
Labelled ligands [3H]fMet-Leu-Phe (Agonist) [1137] [3H]LXA4 (Agonist) [600, 601]
Comments A FITC-conjugated fMLP analogue has been used for binding to the mouse recombinant receptor [833].

Comments

Note that the data for FPR2/ALX are also reproduced on the leukotriene receptor page.

Further reading on Formylpeptide receptors

Dorward DA et al. (2015) The Role of Formylated Peptides and Formyl Peptide Receptor 1 in Governing Neutrophil Function during Acute Inflammation. Am. J. Pathol. 185: 1172-1184 [PMID:25791526]

Dufton N et al. (2010) Therapeutic anti-inflammatory potential of formyl-peptide receptor agonists. Pharmacol. Ther. 127: 175-88 [PMID:20546777]

Liu M et al. (2012) G protein-coupled receptor FPR1 as a pharmacologic target in inflammation and human glioblastoma. Int. Immunopharmacol. 14: 283-8 [PMID:22863814]

Rabiet MJ et al. (2011) N-formyl peptide receptor 3 (FPR3) departs from the homologous FPR2/ALX receptor with regard to the major processes governing chemoattractant receptor regulation, expression at the cell surface, and phosphorylation. J. Biol. Chem. 286: 26718-31 [PMID:21543323]

Yazid S et al. (2012) Anti-inflammatory drugs, eicosanoids and the annexin A1/FPR2 anti-inflammatory system. Prostaglandins Other Lipid Mediat. 98: 94-100 [PMID:22123264]

Ye RD et al. (2009) International Union of Basic and Clinical Pharmacology. LXXIII. Nomenclature for the formyl peptide receptor (FPR) family. Pharmacol. Rev. 61: 119-61 [PMID:19498085]

Free fatty acid receptors

Overview

Free fatty acid receptors (FFA, nomenclature as agreed by the NC-IUPHAR Subcommittee on free fatty acid receptors [455, 2039]) are activated by free fatty acids. Long-chain saturated and unsaturated fatty acids (including C14.0 (myristic acid), C16:0 (palmitic acid), C18:1 (oleic acid), C18:2 (linoleic acid), C18:3, (α-linolenic acid), C20:4 (arachidonic acid), C20:5,n-3 (EPA) and C22:6,n-3 (docosahexaenoic acid)) activate FFA1 [239, 958, 1144] and FFA4 receptors [876, 938, 1617], while short chain fatty acids (C2 (acetic acid), C3 (propanoic acid), C4 (butyric acid) and C5 (pentanoic acid)) activate FFA2 [249, 1223, 1591] and FFA3 [249, 1223] receptors. The crystal structure for agonist bound FFA1 has been described [2023].

Nomenclature FFA1 receptor FFA2 receptor
HGNC, UniProt FFAR1, O14842 FFAR2, O15552
Endogenous agonists docosahexaenoic acid [239, 958], α-linolenic acid [239, 958, 1144], oleic acid [239, 958, 1144], myristic acid [239, 958, 1144] propanoic acid [249, 1223, 1591, 1894], acetic acid [249, 1223, 1591, 1894], butyric acid [249, 1223, 1591, 1894], trans-2-methylcrotonic acid [1894], 1-methylcyclopropanecarboxylic acid [1894]
Selective agonists AMG-837 [1286], compound 4 [381], TUG-770 [380], TUG-905 [379], GW9508 (Partial agonist) [238], fasiglifam [1028, 1558, 2023, 2157] TUG-1375 [801]
Selective antagonists GW1100 (pIC50 6) [238, 2038] GLPG0974 (pIC50 8.1) [1546, 1715], CATPB (pIC50 6.5) [927]
Comments A wide range of both saturated and unsaturated fatty acids containing from 6 to 22 carbons have been shown to act as agonists at FFA1 [239, 958, 1144]. Antagonist GW1100 is also an oxytocin receptor antagonist [238]. Fasiglifam, TUG-770 and GW9508 are approximately 100 fold selective for FFA1 over FFA4 [238, 380, 1558]. AMG-837 and the related analogue AM6331 have been suggested to have an allosteric mechanism of action at FFA1, with respect to the orthosteric fatty acid binding site [1286, 2353].
Nomenclature FFA3 receptor FFA4 receptor GPR42
HGNC, UniProt FFAR3, O14843 FFAR4, Q5NUL3 GPR42, O15529
Endogenous agonists propanoic acid [249, 1223, 1894, 2352], butyric acid [249, 1223, 1894, 2352], 1-methylcyclopropanecarboxylic acid [1894] α-linolenic acid [1955], myristic acid [2275], α-linolenic acid [2100] – Rat, oleic acid [2275]
Agonists acetic acid [249, 1223, 1894, 2352]
Selective agonists compound A [1616], TUG-891 [1955], NCG21 [2065]
Comments Beta-hydroxybutyrate has been reported to antagonise FFA3 responses to short chain fatty acids [1095]. A range of FFA3 selective molecules with agonist and antagonist properties, but which bind at sites distinct from the short chain fatty acid binding site (i.e. allosteric modulators), have been described [196, 926, 1337]. A wide range of both saturated and unsaturated fatty acids containing from 6 to 22 carbons have been shown to act as agonists at FFA4 [382] with a small subset listed above. Compound A [PMID 24997608] exhibits more than 1000 fold selectivity [1616], and TUG-891 50-1000 fold selectivity for FFA4 over FFA1 [1955], dependent on the assay. NGC21 exhibits approximately 15 fold selectivity for FFA4 over FFA1 [2057].

Comments

Short (361 amino acids) and long (377 amino acids) splice variants of human FFA4 have been reported [1490], which differ by a 16 amino acid insertion in intracellular loop 3, and exhibit differences in intracellular signalling properties in recombinant systems [2275]. The long FFA4 splice variant has not been identified in other primates or rodents to date [876, 1490].

GPR42 was originally described as a pseudogene within the family (ENSFM00250000002583), but the discovery of several polymorphisms suggests that some versions of GPR42 may be functional [1276]. GPR84 is a structurally-unrelated G protein-coupled receptor which has been found to respond to medium chain fatty acids [2254].

Further reading on Free fatty acid receptors

Bolognini D et al. (2016) The Pharmacology and Function of Receptors for Short-Chain Fatty Acids. Mol. Pharmacol. 89: 388-98 [PMID:26719580]

Mancini AD et al. (2013) The fatty acid receptor FFA1/GPR40 a decade later: how much do we know? Trends Endocrinol. Metab. 24: 398-407 [PMID:23631851]

Milligan G et al. (2017) Complex Pharmacology of Free Fatty Acid Receptors. Chem. Rev. 117: 67-110 [PMID:27299848]

Moniri NH. (2016) Free-fatty acid receptor-4 (GPR120): Cellular and molecular function and its role in metabolic disorders. Biochem. Pharmacol. 110-111: 1-15 [PMID:26827942]

Stoddart LA et al. (2008) International Union of Pharmacology. LXXI. Free fatty acid receptors FFA1, -2, and -3: pharmacology and pathophysiological functions. Pharmacol. Rev. 60: 405-17 [PMID:19047536]

Watterson KR et al. (2014) Treatment of type 2 diabetes by free Fatty Acid receptor agonists. Front Endocrinol (Lausanne) 5: 137 [PMID:25221541]

GABAB receptors

Overview

Functional GABAB receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on GABAB receptors [215, 1710]) are formed from the heterodimerization of two similar 7TM subunits termed GABAB1 and GABAB2 [215, 557, 1709, 1710, 2173]. GABAB receptors are widespread in the CNS and regulate both pre- and postsynaptic activity. The GABAB1 subunit, when expressed alone, binds both antagonists and agonists, but the affinity of the latter is generally 10-100fold less than for the native receptor. Co-expression of GABAB1 and GABAB2 subunits allows transport of GABAB1 to the cell surface and generates a functional receptor that can couple to signal transduction pathways such as high-voltage-activated Ca2+ channels (Cav2.1, Cav2.2), or inwardly rectifying potassium channels (Kir3) [159,