THE CONCISE GUIDE TO PHARMACOLOGY 2017/18: G protein‐coupled receptors

The Concise Guide to PHARMACOLOGY 2017/18 provides concise overviews of the key properties of nearly 1800 human drug targets with an emphasis on selective pharmacology (where available), plus links to an open access knowledgebase 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.13878/full. G protein‐coupled receptors are one of the eight major pharmacological targets into which the Guide is divided, with the others being: ligand‐gated ion channels, voltage‐gated ion channels, other 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‐2017, and supersedes data presented in the 2015/16 and 2013/14 Concise Guides and previous Guides to Receptors and Channels. It is produced in close conjunction with the Nomenclature Committee of the Union of Basic and Clinical Pharmacology (NC‐IUPHAR), therefore, providing official IUPHAR classification and nomenclature for human drug targets, where appropriate.


Orphans
87 (54)  33 11 a Numbers in brackets refer to orphan receptors for which an endogenous ligand has been proposed in at least one publication, see [414]; b [1511]; c [1362]; d [1941]. 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 β 2 adrenoceptor, the latter culminating in the award of the 2012 Nobel Prize in chemistry to Robert Lefkowitz andBrian Kobilka [1021, 1137].

G protein-coupled receptors → Orphan and other 7TM receptors → Class A Orphans
Overview: Table 1 lists a number of putative GPCRs identified by NC-IUPHAR [557], 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 [414]. 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.  GPR1  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).
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 [1516].
Gene disruption results in increased severity of functional decompensation following aortic banding [10]. Identified as a susceptibility locus for osteoarthritis [520,975,2011]. - Has been reported to activate adenylyl cyclase constitutively through G s [923]. Gpr26 knockout mice show increased levels of anxiety and depression-like behaviours [2209].
Knockdown of Gpr27 reduces endogenous mouse insulin promotor activity and glucose-stimulated insulin secretion [1059]. resolvin D1 has been demonstrated to activate GPR32 in two publications [331,1052]. The pairing was not replicated in a recent study based on arrestin recruitment [1854]. GPR32 is a pseudogene in mice and rats. See reviews [258] and [414].
Reported to associate and regulate the dopamine transporter [1269] and to be a substrate for parkin [1267]. Gene disruption results in altered striatal signalling [1268]. The peptides prosaptide and prosaposin are proposed as endogenous ligands for GPR37 and GPR37L1 [1324].

Comments
The peptides prosaptide and prosaposin are proposed as endogenous ligands for GPR37 and GPR37L1 [1324].
Zn 2+ has been reported to be a potent and efficacious agonist of human, mouse and rat GPR39 [2176]. 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 [285]. Gene disruption results in obesity and altered adipocyte metabolism [1567]. Reviewed in [414].
-GPR50 is structurally related to MT 1 and MT 2 melatonin receptors, with which it heterodimerises constitutively and specifically [1155]. Gpr50 knockout mice display abnormal thermoregulation and are much more likely than wild-type mice to enter fasting-induced torpor [117]. Comments First small molecule agonist reported [1774].
sphingosine 1-phosphate and dioleoylphosphatidic acid have been reported to be low affinity agonists for GPR63 [1459] but this finding was not replicated in an arrestin-based assay [2182].
GPR4, GPR65, GPR68 and GPR132 are now thought to function as proton-sensing receptors detecting acidic pH [414,1775]. Reported to activate adenylyl cyclase; gene disruption leads to reduced eosinophilia in models of allergic airway disease [1044].
CCL5 (CCL5, P13501) was reported to be an agonist of GPR75 [856], but the pairing could not be repeated in an arrestin assay [1854].
GPR78 has been reported to be constitutively active, coupled to elevated cAMP production [923].
-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 [507].
Proposed to regulate hippocampal neurogenesis in the adult, as well as neurogenesis-dependent learning and memory [319].
Mutations in GPR101 have been linked to gigantism and acromegaly [1982].
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 [2193].

GPR160, Q9UJ42
Comments -Gpr149 knockout mice displayed increased fertility and enhanced ovulation, with increased levels of FSH receptor and cyclin D2 mRNA levels [491].
--- --Comments A C-terminal truncation (deletion) mutation in Gpr161 causes congenital cataracts and neural tube defects in the vacuolated lens (vl) mouse mutant [1289]. The mutated receptor is associated with cataract, spina bifida and white belly spot phenotypes in mice [1039]. Gene disruption is associated with a failure of asymmetric embryonic development in zebrafish [1151].
-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 [654].
-S e e [ 859] which discusses characterization of agonists at this receptor.
-Rat GPR182 was first proposed as the adrenomedullin receptor [947]. However, it was later reported that rat and human GPR182 did not respond to adrenomedullin [973] and GPR182 is not currently considered to be a genuine adrenomedullin receptor [756].
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 [277,426,1686]. Gene disruption leads to multiple developmental disorders [911,1219,1849,2092].

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-Pro 7 -angiotensin-(1-7), β-alanine and PD123319 [1102]. Genetic ablation of MRGPRD+ neurons of adult mice decreased behavioural sensitivity to mechanical stimuli but not to thermal stimuli [292]. See reviews [414] and [1847].
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 [1667], also confirmed in an independent study using an arrestin recruitment assay [1854]. See reviews [414] and [1847].
TAAR3 is thought to be a pseudogene in man though functional in rodents [414].
--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 [2023].

Class C Orphans
G protein-coupled receptors → Orphan and other 7TM receptors → Class C Orphans Comments -------G P R C 6 i s a r e l a t e d G q -coupled receptor which responds to basic amino acids [2090].

Taste 1 receptors
G protein-coupled receptors → Orphan and other 7TM receptors → 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 [2215], TRPM5 [2215] and IP3 [802] receptors in post-receptor 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 [1162]. T1R2/T1R3 heterodimers respond to sugars, such as sucrose, and artificial sweeteners, such as saccharin [1440]. 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 [302], while T2R14 responded to at least eight different bitter tastants, including (-)-α-thujone and picrotoxinin [124].
Specialist database BitterDB contains additional information on bitter compounds and receptors [2113].

Further reading on Adenosine receptors
Fredholm BB et al. (2011)  Adhesion Class GPCRs G protein-coupled receptors → 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 autoproteolysis-inducing (GAIN) domain [56] containing a GPCR proteolytic site. The N-terminus often shares structural homology with proteins such as lectins and immunoglobulins, leading to the term adhesion GPCR [571,2187]. The nomenclature of these receptors was revised in 2015 as recommended by NC-IUPHAR and the Adhesion GPCR Consortium [718].
Comments -----A mutation destabilizing the GAIN domain sensitizes mast cells to IgE-independent vibration-induced degranulation [202].  Nomenclature  ADGRG6  ADGRG7  ADGRL1  ADGRL2  ADGRL3  ADGRL4  ADGRV1 HGNC, UniProt u n c t i o n m u t a t i o n s a r e associated with Usher syndrome, a sensory deficit disorder [885].

Comments
The agonists indicated have less than two orders of magnitude selectivity [85].
Recombinant α 1D -adrenoceptors have been shown in some heterologous systems to be mainly located intracellularly but cell-surface localization is encouraged by truncation of the N-terminus, or by co-expression of α 1B -or β 2 -adrenoceptors [706,1993].
In blood vessels all three α 1-adrenoceptor subtypes are located on the surface and intracellularly [1320,1321].
Signalling is predominantly via G q/11 but α 1 -adrenoceptors also couple to G i/o , G s and G 12/13 . Several α 1A -adrenoceptor agonists display ligand directed signalling bias relative to noradrenaline [521]. 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, α 1D -conveying greater agonist sensitivity than α 1A -adrenoceptors [553]. Adrenoceptors, α 2 ARC-239 and prazosin show selectivity for α 2B -and α 2Cadrenoceptors over α 2A -adrenoceptors.Oxymetazoline is a reduced efficacy imidazoline agonist but also binds to non-GPCR binding sites for imidazolines, classified as I 1 , I 2 and I 3 sites [406]; catecholamines have a low affinity, while rilmenidine and moxonidine are selective ligands evoking hypotensive effects in vivo. I 1 -imidazoline receptors cause central inhibition of sympathetic tone, I 2 -imidazoline receptors are an allosteric binding site on monoamine oxidase B, and I 3 -imidazoline receptors regulate insulin secretion from pancreatic β-cells. α 2A -adrenoceptor stimulation reduces insulin secretion from β-islets [2171], 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 [1673]. α 2A -and α 2C -adrenoceptors form homodimers [1829]. Heterodimers between α 2A -and either the α 2c -adrenoceptor or μ opioid peptide receptor exhibit altered signalling and trafficking properties compared to the individual receptors [1829,1931,2036]. Signalling by α 2 -adrenoceptors is primarily via G i/o , although the α 2A -adrenoceptor also couples to G s [487]. Imidazoline compounds display bias relative to each other at the α 2A -adrenoceptor [1544]. The noradrenaline reuptake inhibitor desipramine acts directly on the α 2A -adrenoceptor to promote internalisation via recruitment of arrestin [385]. Adrenoceptors, β [ 125 I]ICYP can be used to define β 1 -or β 2 -adrenoceptors when conducted in the presence of a β 1 -or β 2 -adrenoceptor-selective antagonist. A fluorescent analogue of CGP 12177 can be used to study β 2 -adrenoceptors in living cells [88]. [ 125 I]ICYP at higher (nM) concentrations can be used to label β 3 -adrenoceptors in systems with few if any other β-adrenoceptor subtypes. The β 3 -adrenoceptor has an intron in the coding region, but splice variants have only been described for the mouse [522], where the isoforms display different signalling characteristics [850]. There are 3 β-adrenoceptors in turkey (termed the tβ, tβ3c and tβ4c) that have a pharmacology that differs from the human β-adrenoceptors [86]. 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 [1169]. All β-adrenoceptors couple to G s (activating adenylyl cyclase and elevating cAMP levels), but also activate G i and β-arrestin-mediated signalling. Many β 1 -and β 2 -adrenoceptor antagonists are agonists at β 3adrenoceptors (CL316243, CGP 12177 and carazolol). Many 'antagonists' of cAMP accumulation, for example carvedilol and bucindolol, weakly activate MAP kinase pathways [89,523,589,590,1721,1722] and thus display 'protean agonism'. Bupranolol acts as a neutral antagonist in most systems so far examined. Agonists also display biased signalling at the β 2 -adrenoceptor via G s or arrestins [470]. X-ray crystal structures have been described of the agonist bound [2075] and antagonist bound forms of the β 1 -[2076], agonist-bound [328] and antagonist-bound forms of the β 2 -adrenoceptor [1632,1672], as well as a fully active agonistbound, G s protein-coupled β 2 -adrenoceptor [1633]. Carvedilol and bucindolol bind to a site on the β 1 -adrenoceptor involving contacts in TM2, 3, and 7 and extracellular loop 2 that may facilitate coupling to arrestins [2076]. Compounds displaying arrestinbiased signalling at the β 2 -adrenoceptor have a greater effect on the conformation of TM7, whereas full agonists for G s coupling promote movement of TM5 and TM6 [1192]. Recent studies using NMR spectroscopy demonstrate significant conformational flexibility in the β 2 -adrenoceptor that is stabilized by both agonist and G proteins highlighting the dynamic nature of interactions with both ligand and downstream signalling partners [992,1260,1479]. 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) [425,2021], angiotensin III (AGT, P01019) [425] angiotensin III (AGT, P01019) [394,425,2105], angiotensin II (AGT, P01019) [425,1838,2105], angiotensin-(1-7) (AGT, P01019) [194] Selective agonists L-162,313 [1559] CGP42112 [194] Comments: AT 1 receptors are predominantly coupled to G q/11 , however they are also linked to arrestin recruitment and stimulate G protein-independent arrestin signalling [1221]. Most species express a single AGTR1 gene, but two related agtr1a and agtr1b receptor genes are expressed in rodents. The AT 2 receptor counteracts several of the growth responses initiated by the AT 1 receptors. The AT 2 receptor is much less abundant than the AT 1 receptor in adult tissues and is upregulated in pathological conditions. AT 1 receptor antagonists bearing substituted 4-phenylquinoline moieties have been synthesized, which bind to AT 1 receptors with nanomolar affinity and are slightly more potent than losartan in functional studies [275]. The antagonist activity of CGP42112 at the AT 2 receptor has also been reported [1469]. The AT 1 and bradykinin B 2 receptors have been proposed to form a heterodimeric complex [3]. There is also evidence for an AT 4 receptor that specifically binds angiotensin IV (AGT, P01019) and is located in the brain and kidney. An additional putative endogenous ligand for the AT 4 receptor has been described (LVV-hemorphin (HBB, P68871), a globin decapeptide) [1351].

Further reading on Angiotensin receptors
de Gasparo M et al. (2000) [1938]. A second family of peptides dis-covered independently and named Elabela [338] or Toddler, that has little sequence similarity to apelin, has been proposed as a second endogenous apelin receptor ligand [1542]. Comments: Potency order determined for heterologously expressed human apelin receptor (pD 2 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 [293]. A modified apelin-13 peptide, apelin-13(F13A) was reported to block the hypotensive response to apelin in rat in vivo [1132], however, this peptide exhibits agonist activity in HEK293 cells stably expressing the recombinant apelin receptor [529].

Further reading on Apelin receptor
Cheng B et al. (2012) Neuroprotection of apelin and its signaling pathway. Comments: The triterpenoid natural product betulinic acid has also been reported to inhibit inflammatory signalling through the NFκB pathway [1916]. Disruption of GPBA expression is reported to protect from cholesterol gallstone formation [2031]. A new series of 5-phenoxy-1,3-dimethyl-1H-pyrazole-4-carboxamides have been reported as highly potent agonists [1204].
A physiological role for the BB 3 receptor has yet to be fully defined although recently studies using receptor knockout mice and newly described agonists/antagonists suggest an important role in glucose and insulin regulation, metabolic homeostasis, feeding, regulation of body temperature and other CNS behaviors, obesity, diabetes mellitus and growth of normal/neoplastic tissues [659,1249,1249,1496,1496,2145].

Calcitonin receptors G protein-coupled receptors → 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 [755,1600]) 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 [1600], 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 [952]. Olcegepant (also known as BIBN4096BS, pKi˜10.5) and telcagepant (also known as MK0974, pKi˜9) 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.
The ligands described have limited selectivity. Adrenomedullin has appreciable affinity for CGRP receptors. CGRP can show significant cross-reactivity at AMY receptors and AM 2 receptors. Adrenomedullin 2/intermedin also has high affinity for the AM 2 receptor [818]. CGRP-(8-37) acts as an antagonist of CGRP (pK i8 ) and inhibits some AM and AMY responses (pK i˜6 -7). It is weak at CT receptors. Human AM-(22-52) has some selectivity towards AM receptors, but with modest potency (pK i˜7 ), limiting its use [754]. Olcegepant shows the greatest selectivity between receptors but still has significant affinity for AMY 1 receptors [2057]. G s is a prominent route for effector coupling for CLR and CTR but other pathways (e.g. Ca 2+ , ERK, Akt), and G proteins can be activated [2056]. There is evidence that CGRP-RCP (a 148 amino-acid hydrophilic protein, ASL (P04424) is important for the coupling of CLR to adenylyl cyclase [524]. [ 125 I]-Salmon CT is the most common radioligand for CT receptors but it has high affinity for AMY receptors and is also poorly reversible. [ 125 I]-Tyr 0 -CGRP is widely used as a radioligand for CGRP receptors.

Calcium-sensing receptor G protein-coupled receptors → Calcium-sensing receptor
Overview: The calcium-sensing receptor (CaS, provisional nomenclature as recommended by NC-IUPHAR [557]) 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 [1122]). While divalent/trivalent cations, polyamines and polycations are CaS receptor agonists [234,1618], L-amino acids, glutamyl peptides, ionic strength and pH are allosteric modulators of agonist function [375,557,803,1616,1617]. Indeed, L-amino acids have been identified as "co-agonists", with both concomitant calcium and L-amino acid binding required for full receptor activation [623,2205]. The sensitivity of the CaS receptor to primary agonists is increased by elevated extracellular pH [270] or decreased extracellular ionic strength [1617]. This receptor bears no sequence or structural relation to the plant calcium receptor, also called CaS.

Nomenclature
CaS receptor 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) [375] Cation rank order of potency [234] Glutamyl peptide rank order of potency 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 [728]. 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) [728] and in Casr null mice [307,803], 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 [728]. The CaS receptor primarily couples to G q/11 , G 12/13 and G i/o [418,634,836,1954], but in some cell types can couple to G s [1258]. However, the CaS receptor can form heteromers with Class C GABAB [308,327] and mGlu1/5 receptors [595], which may introduce further complexity in its signalling capabilities. Multiple other small molecule chemotypes are positive and negative allosteric modulators of the CaS receptor [980,1441]. Further, etelcalcetide is a novel peptide agonist of the receptor [2059]. 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 [1443]. Negative allosteric modulators are called calcilytics and can act to increase PTH (PTH, P01270) secretion [1442].
Where functional pK B 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 pK B may differ depending on the signalling pathway studied. Consult the 'More detailed page' for the assay description, as well as other functional readouts.  [1564]) 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 [35]. There are currently three licenced cannabinoid medicines each of which contains a compound that can activate CB 1 and CB 2 receptors [1562]. Two of these medicines were developed to suppress nausea and vomiting produced by chemotherapy. These are nabilone (Cesamet®), a synthetic CB 1 /CB 2 receptor agonist, and synthetic 9 -tetrahydrocannabinol (Marinol®; dronabinol), which can also be used as an appetite stimulant. The third medicine, Sativex®, contains mainly 9 -tetrahydrocannabinol and cannabidiol, both extracted from cannabis, and is used to treat multiple sclerosis and cancer pain.  1852]). Anandamide is also an agonist at vanilloid receptors (TRPV1) and PPARs [1484]. There is evidence for an allosteric site on the CB 1 receptor [1603]. All of the compounds listed as antagonists behave as inverse agonists in some bioassay systems [1564]. For some cannabinoid receptor ligands, additional pharmacological targets that include GPR55 and GPR119 have been iden-tified [1564]. Moreover, GPR18, GPR55 and GPR119, although showing little structural similarity to CB 1 and CB 2 receptors, respond to endogenous agents that are structurally similar to the endogenous cannabinoid ligands [1564].

Overview:
The chemerin receptor (nomenclature as recommended by NC-IUPHAR [414]) is activated by the lipid-derived, anti-inflammatory ligand resolvin E1 (RvE1), which is the result of sequential metabolism of EPA by aspirin-modified cyclooxygenase and lipoxygenase [60,61]. In addition, two GPCRs for resolvin D1 (RvD1) have been identified, FPR2/ALX, the lipoxin A 4 receptor, and GPR32, an orphan receptor [1052]. ) 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. 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 [81]. 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 re-ceptors [82]. Listed are those human agonists with EC 50 values <50nM in either Ca 2+ flux or chemotaxis assays at human recombinant G protein-coupled chemokine receptors expressed in mammalian cell lines. 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 both standard chemokine receptor names [2191] and aliases. Numerical data quoted are typically pK i or pIC 50 [1471]) 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 recep-tors, CCK 1 and CCK 2 receptors [1038,2073], with some alternatively spliced forms most often identified in neoplastic cells. The CCK receptor subtypes are distinguished by their peptide selectivity, with the CCK 1 receptor requiring the carboxyl-terminal heptapeptide-amide that includes a sulfated tyrosine for high affinity and potency, while the CCK 2 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.  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 CCK 2 receptor in which intron 4 is retained, adding 69 amino acids to the intracel-lular loop 3 (ICL3) region, has been described to be present particularly in certain neoplasms where mRNA mis-splicing has been commonly observed [1833], but it is not clear that this receptor splice form plays a special role in carcinogenesis. Another alternative splicing event for the CCK 2 receptor was reported [1850], 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.  [300], 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 [1747]. FZDs are activated by WNTs, which are cysteine-rich lipoglycoproteins with fundamental functions in ontogeny 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. β-Catenin-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 [447], the elevation of intracellular calcium [1828], activation of cGMP-specific PDE6 [19] and elevation of cAMP as well as RAC-1, JNK, Rho and Rho kinase signalling [730]. Furthermore, the phosphoprotein Dishevelled constitutes a key player in WNT/FZD signalling. As with other GPCRs, members of the Frizzled family are functionally dependent on the arrestin scaffolding protein for internalization [321], as well as for β-catenin-dependent [242] and -independent [243, 986] 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. Selective antagonists ---vismodegib (pK i 7.8) [2065] 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 the coupling to G proteins is incomplete (see [447]). There is also a scarcity of information on basic pharmacological characteristics of FZDs, such as binding constants, ligand specificity or concentrationresponse relationships [984].  Comments: SB290157 has also been reported to have agonist properties at the C3a receptor [1282]. The putative chemoattractant receptor termed C5a 2 (also known as GPR77, C5L2) binds [ 125 I]C5a with no clear signalling function, but has a putative role opposing inflammatory responses [267,599,616]. Binding to this site may be displaced with the rank order C5a des-Arg (C5)> C5a (C5, P01031) [267,1508] while there is controversy over the abil-ity of C3a (C3, P01024) and C3a des Arg (C3, P01024) to compete [817,936,937,1508]. C5a 2 appears to lack G protein signalling and has been termed a decoy receptor [1753]. However, C5a 2 does recruit arrestin after ligand binding, which might provide a signaling pathway for this receptor [94,2015], and forms heteromers with C5a 1 . C5a, but not C5a-des Arg, induces upregulation of heteromer formation between complement C5a receptors C5a 1 and C5a 2 [395]. There are also reports of pro-inflammatory activity of C5a 2 , mediated by HMGB1, but the signaling pathway that underlies this is currently unclear (reviewed in [1161]). More recently, work in T cells has shown that C5a 1 and C5a 2 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 C5a 2 ), can affect the final cellular response [57].  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) [1558].   [1897,1962] dopamine [252,573,1725] Agonists fenoldopam [1962] rotigotine [448], cabergoline (Partial agonist) [1337], aripiprazole (Partial agonist) [2199], bromocriptine [573,1337,1725], MLS1547 (Biased agonist) [572], ropinirole [766], apomorphine (Partial agonist) [252,573,1337,1725,1844], pramipexole [1332,1725], benzquinamide [677] [1897,1962] quinpirole [252,1332,1539,1844,1846,2019] Selective agonists SKF-83959 (Biased agonist) [377], SKF-81297 [47] -Rat sumanirole [1301] Antagonists flupentixol (pK i 7-8.4) [1897,1962] blonanserin (pK i 9.9) [1487], pipotiazine (pK i 9.7) [1845], perphenazine (pK i 8.9-9.6) [1055,1761], risperidone (pK i 9.4) [64], perospirone (pK i 9.2) [1762], trifluoperazine (pK i 8.9-9) [1055,1763] Sub/family-selective antagonists SCH-23390 (pK i 7.4-9.5) [1897,1962], SKF-83566 (pK i 9.5) [1897], ecopipam (pK i 8.3) [1963] haloperidol (pK i 7.4-8.8) [573,1230,1332,1844,1963] Selective antagonists -L-741,626 (pK i 7.9-8.5) [688,1069], domperidone (pK i 7.

Comments:
The selectivity of many of these agents is less than two orders of magnitude.  Comments: Splice variants of the ET A receptor have been identified in rat pituitary cells; one of these, ET A R-C13, appeared to show loss of function with comparable plasma membrane expression to wild type receptor [748]. Subtypes of the ET B receptor have been proposed, although gene disruption studies in mice suggest that only a single gene product exists [1350]. G protein-coupled estrogen receptor G protein-coupled receptors → G protein-coupled estrogen receptor

Further reading on Endothelin receptors
Overview: The G protein-coupled estrogen receptor (GPER, nomenclature as agreed by the NC-IUPHAR Subcommittee on the G protein-coupled estrogen receptor [1607]) was identified following observations of estrogen-evoked cyclic AMP signalling in breast cancer cells [65], which mirrored the differential expression of an orphan 7-transmembrane receptor GPR30 [276]. There are observations of both cell-surface and intracellular expression of the GPER receptor [1647,1953].

Further reading on G protein-coupled estrogen receptor
Prossnitz ER et al. (2015)   (butyric acid) and C5 (pentanoic acid)) activate FFA2 [231,1117,1465] and FFA3 [231,1117] receptors. The crystal structure for agonist bound FFA1 has been described [1862]. propanoic acid [231,1117,1465,1741], acetic acid [231,1117,1465,1741], butyric acid [231,1117,1465,1741], trans-2-methylcrotonic acid [1741], 1-methylcyclopropanecarboxylic acid [1741] Selective agonists AMG-837 [1176], compound 4 [347], TUG-770 [346], TUG-905 [345], GW9508 (Partial agonist) [222], fasiglifam [935,1434,1862,1985] [795,1372]. GPR42 was originally described as a pseudogene within the family (ENSFM00250000002583), but the discovery of several polymor-phisms suggests that some versions of GPR42 may be functional [1167]. GPR84 is a structurally-unrelated G protein-coupled receptor which has been found to respond to medium chain fatty acids [2067]. Overview: Functional GABA B receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on GABA B receptors [199,1579]) are formed from the heterodimerization of two similar 7TM subunits termed GABA B1 and GABA B2 [199,506,1578,1579,2002]. GABA B receptors are widespread in the CNS and regulate both pre-and postsynaptic activity. The GABA B1 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 GABA B1 and GABA B2 subunits allows transport of GABA B1 to the cell sur-face and generates a functional receptor that can couple to signal transduction pathways such as high-voltage-activated Ca 2+ channels (Ca v 2.1, Ca v 2.2), or inwardly rectifying potassium channels (Kir3) [147,199,200]. The GABA B1 subunit harbours the GABA (orthosteric)-binding site within an extracellular domain (ECD)  [199,622,624,1578]. The two subunits interact by direct allosteric coupling [1367], such that GABA B2 increases the affinity of GABA B1 for agonists and reciprocally GABA B1 facilitates the coupling of GABA B2 to G proteins [622,1060,1578]. GABA B1 and GABA B2 subunits assemble in a 1:1 stoichiometry by means of a coiled-coil interaction between α-helices within their carboxy-termini that masks an endoplasmic reticulum retention motif (RXRR) within the GABA B1 subunit but other domains of the proteins also contribute to their heteromerization [147,250,1578]. Recent evidence indicates that higher order assemblies of GABA B receptor comprising dimers of heterodimers occur in recombinant expression systems and in vivo and that such complexes exhibit negative functional cooperativity between heterodimers [373,1577]. Adding further complexity, KCTD (potassium channel tetramerization proteins) 8, 12, 12b and 16 associate as tetramers with the carboxy terminus of the GABA B2 subunit to impart altered signalling kinetics and agonist potency to the receptor complex [108, 1751,1990] and are reviewed by [1580]. The molecular complexity of GABAB receptors is further increased through association with trafficking and effector proteins [ and GABA B1b isoforms, which are most prevalent in neonatal and adult brain tissue respectively, differ in their ECD sequences as a result of the use of alternative transcription initiation sites. GABA B1a -containing heterodimers localise to distal axons and mediate inhibition of glutamate release in the CA3-CA1 terminals, and GABA release onto the layer 5 pyramidal neurons, whereas GABA B1b -containing receptors occur within dendritic spines and mediate slow postsynaptic inhibition [1613,2035]. Only the 1a and 1b variants are identified as components of native receptors [199]. Additional GABA B1 subunit isoforms have been described in rodents and humans [1130] and reviewed by [147].  [199,580,581]. Radioligand K D values relate to binding to rat brain membranes. CGP 71872 is a photoaffinity ligand for the GABA B1 subunit [128]. CGP27492 (3-APPA), CGP35024 (3-APMPA) and

Nomenclature
CGP 44532 act as antagonists at human GABA A ρ1 receptors, with potencies in the low micromolar range [580]. In addition to the ligands listed in the table, Ca 2+ binds to the VTM of the GABA B1 subunit to act as a positive allosteric modulator of GABA [594]. Synthetic positive allosteric modulators with low, or no, intrinsic activity include CGP7930, GS39783, BHF-177 [2040] and (+)-BHFF [9,147,154,580]. The site of action of CGP7930 and GS39783 appears to be on the heptahelical domain of the GABA B2 subunit [483,1578]. In the presence of CGP7930 or GS39783, CGP 35348 and 2-hydroxy-saclofen behave as partial agonists [580]. A negative allosteric modulator of GABA B activity has been reported [318]. Knock-out of the GABA B1 subunit in C57B mice causes the development of severe tonic-clonic convulsions that prove fatal within a month of birth, whereas GABA B1 -/-BALB/c mice, although also displaying spontaneous epileptiform activity, are viable. The phenotype of the latter animals additionally includes hyperalgesia, hyperlocomotion (in a novel, but not familiar, environment), hyperdopaminergia, memory impairment and behaviours indicative of anxiety [510,2008]. A similar phenotype has been found for GABA B2 -/-BALB/c mice [613].   [525]; in other species, it is 29 amino acids long and C-terminally amidated. Amino acids 1-14 of galanin are highly conserved in mammals, birds, reptiles, amphibia and fish. Shorter peptide species (e.g. human galanin-1-19 [143] and porcine galanin-5-29 [1809]) and N-terminally extended forms (e.g. N-terminally seven and nine residue elongated forms of porcine galanin [144,1809]) have been reported. galanin-(1-11) is a high-affinity agonist at GAL 1 /GAL 2 (pK i 9), and galanin(2-11) is selective for GAL 2 and GAL 3 compared with GAL 1 [1212]. 26 ]galanin binds to all three subtypes with K d values generally reported to range from 0.05 to 1 nM, depending on the assay conditions used [552,1821,1834,1835,2070]. Porcine galanin-(3-29) does not bind to cloned GAL 1 , GAL 2 or GAL 3 receptors, but a receptor that is functionally activated by porcine galanin-(3-29) has been reported in pituitary and gastric smooth muscle cells [691,2142]. Additional galanin receptor subtypes are also suggested from studies with chimeric peptides (e.g. M15, M35 and M40), which act as antagonists in functional assays in the cardiovascular system [2000] [552,1834,1835]. Recent studies have described the synthesis of a series of novel, systemically-active, galanin analogues, with modest preferential binding at the GAL 2 receptor. Specific chemical modifications to the galanin backbone increased brain levels of these peptides after i.v. injection and several of these peptides exerted a potent antidepressant-like effect in mouse models of depression [1698]. Ghrelin receptor G protein-coupled receptors → Ghrelin receptor

Overview:
The ghrelin receptor (nomenclature as agreed by the NC-IUPHAR Subcommittee for the Ghrelin receptor [415]) is activated by a 28 amino-acid peptide originally isolated from rat stomach, where it is cleaved from a 117 aminoacid precursor (GHRL, Q9UBU3). The human gene encoding the precursor peptide has 83% sequence homology to rat preproghrelin, although the mature peptides from rat and human differ by only two amino acids [1285]. Alternative splicing results in the formation of a second peptide, [des-Gln 14 ]ghrelin (GHRL, Q9UBU3) with equipotent biological activity [822]. A unique post-translational modification (octanoylation of Ser 3 , catalysed by ghrelin O-acyltransferase (MBOAT4, Q96T53) [2170] occurs in both peptides, essential for full activity in binding to ghrelin receptors in the hypothalamus and pituitary, and for the release of growth hormone from the pituitary [1029]. Structure activity studies showed the first five N-terminal amino acids to be the minimum required for binding [122], and receptor mutagenesis has indicated overlap of the ghrelin binding site with those for small molecule agonists and allosteric modulators of ghrelin (GHRL, Q9UBU3) function [814]. In cell systems, the ghrelin receptor is constitutively active [815], but this is abolished by a naturally occurring mutation (A204E) that results in decreased cell surface receptor expression and is associated with familial short stature [1527].  [121], which raises the possible existence of different receptor subtypes in peripheral tissues and the central nervous system. A potent inverse agonist has been identified ([D-Arg 1 ,D-Phe 5 ,D-Trp 7,9 ,Leu 11 ]substance P, pD 2 8.3; [812]). Ulimorelin, described as a ghrelin receptor agonist (pK i 7.8 and pD 2 7.5 at human recombinant ghrelin receptors), has been shown to stimulate ghrelin receptor mediated food intake and gastric emptying but not elicit release of growth hormone, or modify ghrelin stimulated growth hormone release, thus pharmacolog-ically discriminating the orexigenic and gastrointestinal actions of ghrelin (GHRL, Q9UBU3) from the release of growth hormone [567]. A number of selective antagonists have been reported, including peptidomimetic [1393] and non-peptide small molecules including GSK1614343 [1556,1699].

Comments:
The glucagon receptor has been reported to interact with receptor activity modifying proteins (RAMPs), specifically RAMP2, in heterologous expression systems [349], although the physiological significance of this has yet to be established.  Gonadotrophin-releasing hormone receptors G protein-coupled receptors → Gonadotrophin-releasing hormone receptors Overview: GnRH 1 and GnRH 2 receptors (provisonal nomenclature [557], also called Type I and Type II GnRH receptor, respectively [1342]) have been cloned from numerous species, most of which express two or three types of GnRH receptor [1341, 1342,1810]. GnRH I (GNRH1, P01148) (p-Glu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH2) is a hypothalamic decapeptide also known as luteinizing hormone-releasing hormone, gonadoliberin, luliberin, gonadorelin or simply as GnRH. It is a member of a family of similar peptides found in many species [1341,1342,1810] including GnRH II (GNRH2, O43555) (pGlu-His-Trp-Ser-His-Gly-Trp-Tyr-Pro-Gly-NH 2 (which is also known as chicken GnRH-II). Receptors for three forms of GnRH exist in some species but only GnRH I and GnRH II and their cognate receptors have been found in mammals [1341, 1342,1810]. GnRH 1 receptors are expressed by pituitary gonadotrophs, where they mediate the effects of GnRH on gonadotropin hormone synthesis and secretion that underpin central control of mammalian reproduction. GnRH analogues are used in assisted reproduction and to treat steroid hormone-dependent conditions [981]. Notably, agonists cause desensitization of GnRH-stimulated gonadotropin secretion and the consequent reduction in circulating sex steroids is exploited to treat hormone-dependent cancers of the breast, ovary and prostate [981]. GnRH1 receptors are selectively activated by GnRH I and all lack the COOH-terminal tails found in other GPCRs. GnRH 2 receptors do have COOH-terminal tails and (where tested) are selective for GnRH II over GnRH I. GnRH2 receptors are expressed by some primates but not by humans [1377]. Phylogenetic classifications divide GnRH receptors into three [1342] or five groups [2117] and highlight examples of gene loss through evolution, with humans retaining only one ancient gene.

GPR18, GPR55 and GPR119
G protein-coupled receptors → GPR18, GPR55 and GPR119 Overview: GPR18, GPR55 and GPR119 (provisional nomenclature), although showing little structural similarity to CB 1 and CB 2 cannabinoid receptors, respond to endogenous agents analogous to the endogenous cannabinoid ligands, as well as some natural/synthetic cannabinoid receptor ligands [1564]. Although there are multiple reports to indicate that GPR18, GPR55 and GPR119 can be activated in vitro by N-arachidonoylglycine, lysophosphatidylinositol and N-oleoylethanolamide, respectively, there is a lack of evidence for activation by these lipid messengers in vivo. As such, therefore, these receptors retain their orphan status.

Comments
The pairing of N-arachidonoylglycine with GPR18 was not replicated in two studies based on arrestin assays [1854,2182]. See [414] for discussion.
See reviews [414] and [1800]. In addition to those shown above, further small molecule agonists have been reported [722].
Comments: GPR18 failed to respond to a variety of lipidderived agents in an in vitro screen [2182], but has been reported to be activated by 9 -tetrahydrocannabinol [1308]. GPR55 responds to AM251 and rimonabant at micromolar concentrations, compared to their nanomolar affinity as CB 1 receptor antagonists/inverse agonists [1564]. It has been reported that lysophosphatidylinositol acts at other sites in addition to GPR55 [2164]. N-Arachidonoylserine has been suggested to act as a low efficacy agonist/antagonist at GPR18 in vitro [1306]. It has also been suggested oleoyl-lysophosphatidylcholine acts, at least in part, through GPR119 [1466]. Although PSN375963 and PSN632408 produce GPR119-dependent responses in heterologous expression systems, comparison with N-oleoylethanolamidemediated responses suggests additional mechanisms of action [1466].

Comments:
Further closely-related GPCRs include the 5-oxoeicosanoid receptor (OXER1, Q8TDS5) and GPR31 (O00270). Lactate activates HCA 1 on adipocytes in an autocrine manner. It inhibits lipolysis and thereby promotes anabolic effects. HCA 2 and HCA 3 regulate adipocyte lipolysis and immune functions under conditions of increased FFA formation through lipolysis (e.g., during fasting). HCA 2 agonists acting mainly through the receptor on immune cells exert antiatherogenic and anti-inflammatory effects. HCA 2 is also a receptor for butyrate and mediates some of the beneficial effects of short-chain fatty acids produced by gut microbiota.   The human BLT 1 receptor is the high affinity LTB 4 receptor whereas the BLT 2 receptor in addition to being a low-affinity LTB 4 receptor also binds several other lipoxygenase-products, such as 12S-HETE, 12S-HPETE, 15S-HETE, and the thromboxane synthase product 12-hydroxyheptadecatrienoic acid. The BLT receptors mediate chemotaxis and immunomodulation in several leukocyte populations and are in addition expressed on non-myeloid cells, such as vascular smooth muscle and endothelial cells. In addition to BLT receptors, LTB 4 has been reported to bind to the peroxisome proliferator activated receptor (PPAR) α [1178] and the vanilloid TRPV1 ligand-gated nonselective cation channel [1307]. The receptors for the cysteinyl-leukotrienes (i.e. LTC 4 , LTD 4 and LTE 4 ) are termed CysLT 1 and CysLT 2 and exhibit distinct expression pat-terns in human tissues, mediating for example smooth muscle cell contraction, regulation of vascular permeability, and leukocyte activation. There is also evidence in the literature for additional CysLT receptor subtypes, derived from functional in vitro studies, radioligand binding and in mice lacking both CysLT 1 and CysLT 2 receptors [258]. Cysteinyl-leukotrienes have also been suggested to signal through the P2Y 12 receptor [570,1473,1534], GPR17

Further reading on Hydroxycarboxylic acid receptors
[359] and GPR99 [943].  [330] as well as annexin I (ANXA1, P04083) (ANXA1) and its N-terminal peptides [379,1560]. In addition, a soluble hydrolytic product of protease action on the urokinase-type plasminogen activator receptor has been reported to activate the FPR2/ALX receptor [1646]. Furthermore, FPR2/ALX has been suggested to act as a receptor mediating the proinflammatory actions of the acute-phase reactant, serum amyloid A [1840,1883]. The agonist activity of the lipid mediators described has been questioned [732,1585], which may derive from batch-tobatch differences, partial agonism or biased agonism. Recent results from Cooray et al. (2013) [379] have addressed this issue and the role of homodimers and heterodimers in intracellular signaling. A receptor selective for LXB 4 has been suggested from functional studies [58,1232,1670]. Note that the data for FPR2/ALX are also reproduced on the Formylpeptide receptor pages.

Nomenclature
Oxoeicosanoid receptors (OXE, nomenclature agreed by the NC-IUPHAR subcommittee on Oxoeicosanoid Receptors [219]) are activated by endogenous chemotactic eicosanoid ligands oxidised at the C-5 position, with 5-oxo-ETE the most potent agonist identified for this receptor. Initial characterization of the heterologously expressed OXE receptor suggested that polyunsaturated fatty acids, such as docosahexaenoic acid and EPA, acted as receptor antagonists [823].

Further reading on Leukotriene receptors
Bäck M et al. (2011) [414,983]) are activated by the endogenous phospholipid metabolite LPA. The first receptor, LPA 1 , was identified as ventricular zone gene-1 (vzg-1), leading to deorphanisation of members of the endothelial differentiation gene (edg) family as other LPA receptors along with sphingosine 1-phosphate (S1P) receptors. Additional LPA receptor GPCRs were later identified. Gene names have been codified as LPAR1, etc. to reflect the receptor function of proteins. The crystal structure of LPA 1 was recently solved and demonstrates extracellular LPA access to the binding pocket, consistent with proposed delivery via autotaxin. These studies have also implicated cross-talk with endocannabinoids via phosphorylated intermediates that can also activate these receptors. The identified receptors can account for most, although not all, LPAinduced phenomena in the literature, indicating that a majority of LPA-dependent phenomena are receptor-mediated. Radioligand binding has been conducted in heterologous expression systems using [ 3 H]LPA (e.g. [586]). In native systems, analysis of binding data is complicated by metabolism and high levels of nonspecific binding, and therefore the relationship between recombinant and endogenously expressed receptors is unclear. Targeted deletion of LPA receptors has clarified signalling pathways and identified physiological and pathophysiological roles. Independent valida-tion by multiple groups has been reported in the peer-reviewed literature for all six LPA receptors described in the tables, including further validation using a distinct read-out via a novel TGFα "shedding" assay [864]. LPA has also been described as an agonist for the transient receptor potential (Trp) ion channel TRPV1 [1461] and TRPA1 [1012]. In addition, orphan GPCRs (PSP24 [547] and GPR87 [1488]) are proposed as LPA receptors. LPA was originally proposed to be a ligand for GPCR35, but recent data shows that in fact it is a receptor for CXCL17 (CXCL17, Q6UXB2) [1266]. Further, the nuclear hormone receptor PPARγ [1309,1812], has been reported as an LPA receptor. All of these proposed entities require confirmation and are not currently recognized as bona fide LPA receptors. Lysophospholipid (S1P) receptors G protein-coupled receptors → Lysophospholipid (S1P) receptors Overview: Sphingosine 1-phosphate (S1P) receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on Lysophospholipid receptors [983]) are activated by the endogenous lipid sphingosine 1-phosphate (S1P) and with lower apparent affinity, sphingosylphosphorylcholine (SPC). Originally cloned as orphan members of the endothelial differentiation gene (edg) family, deorphanisation as lysophospholipid receptors for S1P was based on sequence homology to LPA receptors. Current gene names have been codified as S1P 1 R, etc. to reflect the receptor function of these proteins. Most cellular phenomena ascribed to S1P can be explained by receptor-mediated mechanisms; S1P has also been described to act at intracellular sites [1915], and awaits precise definition. Previously-proposed SPC (or lysophophosphatidylcholine) receptors-G2A, TDAG8, OGR1 and GPR4-continue to lack confirmation of these roles [414]. The relationship between recombinant and endogenously expressed receptors is unclear. Radioligand binding has been conducted in heterologous expression systems using [ 32 P]S1P (e.g [1505]). In native systems, analysis of binding data is complicated by metabolism and high levels of nonspecific binding. Targeted dele-tion of several S1P receptors and key enzymes involved in S1P biosynthesis or degradation has clarified signalling pathways and physiological roles. A crystal structure of an S1P 1 -T4 fusion protein has been described [733].
The S1P receptor modulator, fingolimod (FTY720, Gilenya), has received world-wide approval as the first oral therapy for relapsing forms of multiple sclerosis. This drug has a novel mechanism of action involving modulation of S1P receptors in both the immune and nervous systems [340, 369,687], although the precise nature of its interaction requires clarification.
The MT 3 binding site of hamster brain and peripheral tissues such as kidney and testis, also termed the ML 2 receptor, binds selectively 2-iodo-[ 125 I]5MCA-NAT [1356]. Pharmacological investigations of MT 3 binding sites have primarily been conducted in hamster tissues. At this site, The endogenous ligand N-acetylserotonin [495,1215,1356,1588] and 5MCA-NAT [1588] appear to function as agonists, while prazosin [1215] functions as an antagonist. The MT 3 binding site of hamster kidney was also identified as the hamster homologue of human quinone reduc-tase 2 (NQO2, P16083 [1474,1475]). The MT 3 binding site activated by 5MCA-NAT in eye ciliary body is positively coupled to adenylyl cyclase and regulates chloride secretion [842]. Xenopus melanophores and chick brain express a distinct receptor (x420, P49219; c346, P49288, initially termed Mel 1C ) coupled to the G i/o family of G proteins, for which GPR50 has recently been suggested to be a mammalian counterpart [479] although melatonin does not bind to GPR50 receptors. Several variants of the MTNR1B gene have been associated with increased type 2 diabetes risk.  solved [1075,1364,1408,1984]. The structure of the 7 transmembrane (TM) domains of both mGlu1 and mGlu5 have been solved, and confirm a general helical organization similar to that of other GPCRs, although the helices appear more compacted [465,2136]. mGlu form constitutive dimers crosslinked by a disulfide bridge. Although mGlu receptors have been thought to only form homodimers, recent studies revealed the possible formation of heterodimers between either group-I receptors, or within and between group-II and -III receptors [468]. Although well characterized in transfected cells, co-localization and specific pharmacological properties also suggest the existence of such heterodimers in the brain [2183]. The endogenous ligands of mGlu are L-glutamic acid, L-serine-O-phosphate, N-acetylaspartylglutamate (NAAG) and L-cysteine sulphinic acid. Group-I mGlu receptors may be activated by 3,5-DHPG and (S)-3HPG [204] and antagonized by (S)-hexylhomoibotenic acid [1235]. Group-II mGlu receptors may be activated by LY389795 [1365], LY379268 [1365], eglumegad [1744,2138], DCG-IV and (2R,3R)-APDC [1745], and antagonised by eGlu [890] and LY307452 [518,2096]. Group-III mGlu receptors may be activated by L-AP4 and (R,S)-4-PPG [610]. An example of an antagonist selective for mGlu receptors is LY341495, which blocks mGlu 2 and mGlu 3 at low nanomolar concentrations, mGlu 8 at high nanomolar concentrations, and mGlu 4 , mGlu 5 , and mGlu 7 in the micromolar range [1001]. In addition to orthosteric ligands that directly interact with the glutamate recognition site, allosteric modulators that bind within the TM domain have been described. Negative allosteric modulators are listed separately. The positive allosteric modulators most often act as 'potentiators' of an orthosteric agonist response, without significantly activating the receptor in the absence of agonist.
Nomenclature mGlu 1 receptor mGlu 2 receptor mGlu 3 receptor mGlu 4 receptor mGlu 5 receptor Endogenous agonists L-glutamic acid [1574] L-glutamic acid [1574] L-glutamic acid [1574], NAAG [1750] L-glutamic acid [1574] L-glutamic acid [1574] Agonists PCCG-4 (pIC 50 Endogenous agonists L-glutamic acid [1574] L-glutamic acid [1574] L-serine-O-phosphate [1254,2138], L-glutamic acid [1574] Agonists -LSP4-2022 [666], L-serine-O-phosphate [2138], L-AP4 [2138] (S)-3,4-DCPG [1952], L-AP4 [1254] Selective agonists 1-benzyl-APDC [1987 [48] at mGlu 5 receptors. Although a number of radioligands have been used to examine binding in native tissues, correlation with individual subtypes is limited. Many pharmacological agents have not been fully tested across all known subtypes of mGlu receptors. Po-tential differences linked to the species (e.g. human versus rat or mouse) of the receptors and the receptor splice variants are generally not known. The influence of receptor expression level on pharmacology and selectivity has not been controlled for in most studies, particularly those involving functional assays of receptor coupling. (S)-(+)-CBPG is an antagonist at mGlu 1 , but is an agonist (albeit of reduced efficacy) at mGlu 5 receptors. DCG-IV also exhibits agonist activity at NMDA glutamate receptors [2007], and is an antagonist at all Group-III mGluRs with an IC 50 of 30μM. A potential novel metabotropic glutamate receptor coupled to phosphoinositide turnover has been observed in rat brain; it is ac-tivated by 4-methylhomoibotenic acid (ineffective as an agonist at recombinant Group I metabotropic glutamate receptors), but is resistant to LY341495 [356]. There are also reports of a distinct metabotropic glutamate receptor coupled to phospholipase D in rat brain, which does not readily fit into the current classification [1013,1549] A related class C receptor composed of two distinct subunits, T1R1 + T1R3 is also activated by glutamate and is responsible for umami taste detection.
All selective antagonists at metabotropic glutamate receptors are competitive.

Further reading on Metabotropic glutamate receptors
Conn PJ et al. (1997)  , which may also generate a motilin-associated peptide (MLN, P12872). These receptors promote gastrointestinal motility and are suggested to be responsible for the gastrointestinal prokinetic effects of certain macrolide antibiotics (often called motilides; e.g. erythromycin), although for many of these molecules the evidence is sparse.

Nomenclature motilin receptor
Endogenous agonists motilin (MLN, P12872) [386,1286,1287,1288] Agonists alemcinal [1947], erythromycin-A [533,1947], azithromycin [225] Selective agonists camicinal [105,1712], mitemcinal [1023,1918]  Comments: In terms of structure, the motilin receptor has closest homology with the ghrelin receptor. Thus, the human motilin receptor shares 52% overall amino acid identity with the ghrelin receptor and 86% in the transmembrane regions [759,1918,1947]. However, differences between the N-terminus regions of these receptors means that their cognate peptide ligands do not readily activate each other [408,1712]. In laboratory rodents, the gene encoding the motilin percursor appears to be absent, while the receptor appears to be a pseudogene [759,1710]. Functions of motilin (MLN, P12872) are not usually detected in rodents, al-though brain and other responses to motilin and the macrolide alemcinal have been reported and the mechanism of these actions is obscure [1311,1462]. Notably, in some non-laboratory rodents (e.g. the North American kangaroo rat (Dipodomys) and mouse (Microdipodops) a functional form of motilin may exist but the motilin receptor is non-functional [1159]. Marked differences in ligand affinities for the motilin receptor in dogs and humans may be explained by significant differences in receptor structure [1711]. Note that for the complex macrolide structures, selectivity of action has often not been rigorously examined and other ac-tions are possible (e.g. P2X inhibition by erythromycin; [2216]). Small molecule motilin receptor agonists are now described [1159,1712,2100]. The motilin receptor does not appear to have constitutive activity [812]. Although not proven, the existence of biased agonism at the receptor has been suggested [1288,1348,1709]. A truncated 5-transmembrane structure has been identified but this is without activity when transfected into a host cell [533]. Receptor dimerisation has not been reported. has also been identified as an endogenous agonist [1378]. NmS-33 is, as its name suggests, a 33 amino-acid product of a precursor protein derived from a single gene and contains an amidated Cterminal heptapeptide identical to NmU. NmS-33 appears to activate NMU receptors with equivalent potency to NmU-25.
Nomenclature NMU1 receptor NMU2 receptor Antagonists -R-PSOP (pK B 7) [1193] Comments: NMU1 and NMU2 couple predominantly to G q/11 although there is evidence of good coupling to G i/o [218,825,833].  10-fold) than human NPS receptor Asn107 [1645]. Several epidemiological studies reported an association between Asn 107 Ile receptor variant and susceptibility to panic disorders [458,460,1506,1621]. The SNP Asn 107 Ile has also been linked to sleep behavior [662], inflammatory bowel disease [402], schizophrenia [1145], increased impulsivity and ADHD symptoms [1083]. Interestingly, a carboxy-terminal splice variant of human NPS receptor was found to be overexpressed in asthmatic patients [1091].  [584,1792]. C-terminally extended forms of the peptides (neuropeptide W-30 (NPW, Q8N729) and neuropeptide B-29 (NPB, Q8NG41)) also activate NPBW1 [216]. Unique to both forms of neuropeptide B is the N-terminal bromination of the first tryptophan residue, and it is from this post-translational modification that the nomenclature NPB is derived. These peptides were first identified from bovine hypothalamus and therefore are classed as neuropeptides. Endogenous variants of the peptides with-out the N-terminal bromination, des-Br-neuropeptide B-23 (NPB, Q8NG41) and des-Br-neuropeptide B-29 (NPB, Q8NG41), were not found to be major components of bovine hypothalamic tissue extracts. The NPBW2 receptor is activated by the short and C-terminal extended forms of neuropeptide W and neuropeptide B [216].  [2080]. It has been reported that neuropeptide W may have a key role in the gating of stressful stimuli when mice are exposed to novel environments [1392]. Two an-tagonists have been discovered and reported to have affinity for NPBW1, ML181 and ML250, the latter exhibiting improved selectivity ( ∼ 100 fold) for NPBW1 compared to MCH1 receptors [694,695]. Computational insights into the binding of antagonists to this receptor have also been described [1541].  [1330]) are activated by the endogenous peptides neuropeptide Y (NPY, P01303), neuropeptide Y- , peptide YY (PYY, P10082), PYY-  and pancreatic polypeptide (PPY, P01298) (PP). The receptor originally identified as the Y3 receptor has been identified as the CXCR4 chemokine recepter (originally named LESTR, [1201]). The y6 receptor is a functional gene product in mouse, absent in rat, but contains a frameshift mutation in primates producing a truncated non-functional gene [676]. Many of the agonists exhibit differing degrees of selectivity dependent on the species examined. For example, the potency of PP is greater at the rat Y 4 receptor than at the human receptor [513]. In addition, many agonists lack selectiv-ity for individual subtypes, but can exhibit comparable potency against pairs of NPY receptor subtypes, or have not been examined for activity at all subtypes. [  Comments: neurotensin (NTS, P30990) appears to be a lowefficacy agonist at the NTS 2 receptor [2039], while the NTS 1 receptor antagonist meclinertant is an agonist at NTS 2 receptors [2039]. An additional protein, provisionally termed NTS 3 (also known as NTR3, gp95 and sortilin; ENSG00000134243), has been suggested to bind lipoprotein lipase and mediate its degradation [1460]. It has been reported to interact with the NTS 1 receptor [1273] and the NTS 2 receptor [260], and has been implicated in hormone traf-ficking and/or neurotensin uptake. A splice variant of the NTS 2 receptor bearing 5 transmembrane domains has been identified in mouse [195] and later in rat [1561].

Further reading on Neurotensin receptors
Boules M et al. endomorphin-1 and endomorphin-2 are also potential endogenous peptides. The Greek letter nomenclature for the opioid receptors, μ, δ and κ, is well established, and NC-IUPHAR considers this nomenclature appropriate, along with the symbols spelled out (mu, delta, and kappa), and the acronyms, MOP, DOP, and KOP. [390,441,557]. The human N/OFQ receptor, NOP, is considered 'opioid-related' rather than opioid because, while it exhibits a high degree of structural homology with the conventional opioid receptors [1361], it displays a distinct pharmacology. Currently there are numerous clinically used drugs, such as morphine and many other opioid analgesics, as well as antagonists such as naloxone, however only for the μ receptor.  [1972], etorphine [1972], ethylketocyclazocine [1972] levorphanol [727], hydromorphone [2094], fentanyl [1972], buprenorphine (Partial agonist) [1972], methadone [1595], codeine [1972], tapentadol [1992] [1535], these putative isoforms have not been correlated with any of the subtypes of receptor proposed in years past. Opioid receptors may heterodimerize with each other or with other 7TM receptors [926], and give rise to complexes with a unique pharmacology, however, evidence for such heterodimers in native cells is equivocal and the consequences of this heterodimerization for signalling remains largely unknown. For μ-opioid receptors at least, dimerization does not seem to be required for signalling [1078]. A distinct metenkephalin receptor lacking structural resemblance to the opioid receptors listed has been identified (OGFR, 9NZT2) and termed an opioid growth factor receptor [2198].
Endomorphin-1 and endomorphin-2 have been identified as highly selective, putative endogenous agonists for the μ-opioid receptor. At present, however, the mechanisms for endomorphin synthesis in vivo have not been established, and there is no gene identified that encodes for either. Thus, the status of these peptides as endogenous ligands remains unproven.
Two areas of increasing importance in defining opioid receptor function are the presence of functionally relevant single nucleotide polymorphisms in human μ-receptors [1490] and the identification of biased signalling by opioid receptor ligands, in particular, compounds previously characterized as antagonists [236]. Pathway bias for agonists makes general rank orders of potency and efficacy somewhat obsolete, so these do not appear in As ever, the mechanisms underlying the acute and long term regulation of opiod receptor function are the subject of intense investigation and debate. The richness of opioid receptor pharmacology has been enhanced with the recent discovery of allosteric modulators of μ and δ receptors, notably the positive allosteric modulators and silent allosteric "antagonists" outlined in [247,248]. Negative allosteric modulation of opioid receptors has been previously suggested [953], whether all compounds are acting at a similar site remains to be established.

Further reading on Opioid receptors
Butelman ER et al. (2012)  Comments: The primary coupling of orexin receptors to G q/11 proteins is rather speculative and based on the strong activation of phospholipase C, though recent studies in recombinant CHO cells also stress the importance of G q/11 [1065]. Coupling of both receptors to G i/o and G s has also been reported [951,1068,1146,1629] for most cellular responses observed, the G protein pathway is unknown. The potency order of endogenous ligands may depend on the cellular signal transduction machinery. Most of the OX 2 receptor selective antagonists listed are weakly selective (≤10-fold), or selectivity may be less than 100-fold or not unequiv-  [1177]. Antagonists of the orexin receptors are the focus of major drug discovery effort for their potential to treat insomnia and other dis-orders of wakefulness [1668], while agonists would likely be useful in human narcolepsy.

Further reading on Somatostatin receptors
Colao A et al.  Overview: Nomenclature as recommended by NC-IUPHAR [414]. The Succinate receptor has been identified as being activated by physiological levels of the Krebs' cycle intermediate succinate and other dicarboxylic acids such as maleate in 2004. Since its pairing with its endogenous ligand, the receptor has been the focus of intensive research and its role has been evidenced in various (patho)physiological processes such as regulation of renin production, retinal angiogenesis or immune response.

Nomenclature
succinate receptor HGNC, UniProt SUCNR1, Q9BXA5 Endogenous agonists succinic acid [762,1854] Comments: In humans, there is the possibility of two open-reading frames (ORFs) for SUCNR1, allowing the generation of 330 or 334 amino acid proteins Wittenberger et al. [2127] noted that the 330-AA protein was more likely to be expressed given the Kozak sequence surrounding the second ATG. Some databases report SUCNR1 as being 334-AA long.

Further reading on VIP and PACAP receptors
Harmar AJ et al. (1998)