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

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 (http://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.


Receptors with known ligands
33 11 a Numbers 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] 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 Class A Orphans 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 [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. LGR4 LGR5 LGR6 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).  [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].
-Has been reported to activate adenylyl cyclase constitutively through G s [1016]. Gpr26 knockout mice show increased levels of anxiety and depression-like behaviours [2421].

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].

Comments
The peptides prosaptide and prosaposin are proposed as endogenous ligands for GPR37 and GPR37L1 [1438].
Zn 2+ 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 MT 1 and MT 2 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].
-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].
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]. ----

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].
Proposed to regulate hippocampal neurogenesis in the adult, as well as neurogenesis-dependent learning and memory [352].
Mutations in GPR101 have been linked to gigantism and acromegaly [2154].
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].
Comments -Gpr149 knockout mice displayed increased fertility and enhanced ovulation, with increased levels of FSH receptor and cyclin D2 mRNA levels [542].
--- 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]. 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 (2019) 176, S21-S141
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]. 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-Pro 7 -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].
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].

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].
--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].

Class C Orphans
G protein-coupled receptors → Orphan and other 7TM receptors → Class C Orphans Overview: This set contains class C 'orphan' G protein coupled receptors where the endogenous ligand(s) is not known.
GPRC6A, Q5T6X5 C o m m e n t s -------G P R C 6 i s a G q -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. 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.

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. 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].
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].
ADGRF2 is highly expressed in squamous epithelia and gene deficiency did not result in detectable defects [1744].
ADGRF4 couples to G q/11 proteins [482], is highly expressed in squamous epithelia and gene deficiency did not result in detectable defects [1744].
ADGRG4 is highly expressed in enterochromaffin cells and gastrointestinal neuroendocrine tumors [1250].
ADGRG5 is a constitutively active G s protein-coupled receptor [770,2310], highly expressed in eosinophils and NK cells [1682]. relatively selective radioligands. S(+)-niguldipine also has high affinity for L-type Ca 2+ channels. Fluorescent derivatives of prazosin (Bodipy PLprazosin-QAPB) are used to examine cellular localisation of α 1 -adrenoceptors. Selective α 1 -adrenoceptor agonists are used as nasal decongestants; antagonists to treat hypertension (doxazosin, prazosin) and benign prostatic hyperplasia (alfuzosin, tamsulosin). The α 1 -and β 2 -adrenoceptor antagonist carvedilol is used to treat congestive heart failure, although the contribution of α 1 -adrenoceptor blockade to the therapeutic effect is unclear. Several anti-depressants and anti-psychotic drugs are α 1 -adrenoceptor antagonists contributing to side effects such as orthostatic hypotension and extrapyramidal effects.
[ 3 H]rauwolscine, [ 3 H]brimonidine and [ 3 H]RX821002 are relatively selective radioligands. There is species variation in the pharmacology of the α 2A -adrenoceptor. Multiple mutations of α 2 -adrenoceptors have been described, some associated with alterations in function. Presynaptic α 2 -adrenoceptors regulate many functions in the nervous system. The α 2 -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 with-drawal. Dexmedetomidine (also xylazine) is used as a sedative and analgesic in human and veterinary medicine with sympatholytic and anxiolytic properties. The α 2 -adrenoceptor antagonist yohimbine has been used to treat erectile dysfunction and mirtazapine as an anti-depressant. The α 2B subtype appears to be involved in neurotransmission in the spinal cord and α 2C in regulating catecholamine release from adrenal chromaffin cells.

Further reading on Adrenoceptors
Baker JG et al. (2011) Evolution of β-blockers: from anti-anginal drugs to ligand-directed signalling.
Trends 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 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 [1332]. 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 [300]. The antagonist activity of CGP42112 at the AT 2 receptor has also been reported [1596]. The AT 1 and bradykinin B 2 receptors have been proposed to form a heterodimeric complex [3]. β-Arrestin1 prevents AT 1 -B 2 receptor heteromerization [1756]. 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) [1467].

Further reading on Angiotensin receptors
Asada H et al. (2018) [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]. 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 [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].
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 [903]. CGRP-(8-37) acts as an antagonist of CGRP (pK i 8) 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 [829]. Olcegepant shows the greatest selectivity between receptors but still has significant affinity for AMY 1 receptors [2241]. 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 [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].
[ 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.  [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.
The CaS receptor primarily couples to G q/11 , G 12/13 and G i/o [459,693,922,2124], but in some cell types can couple to G s [1370]. However, the CaS receptor can form heteromers with Class C GABA B [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 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.
There are currently three licenced cannabinoid medicines each of which contains a compound that can activate CB 1 and CB 2 receptors [1690]. Two of these medicines were developed to sup-press 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.

Further reading on Chemerin receptors
Kennedy AJ et al. (2018)  ) 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 recep-tor 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 both standard chemokine receptor names [2401] and aliases.    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 [1995], 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 [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  [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 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 [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.

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].

Further reading on G protein-coupled estrogen receptor
Barton M et al. (2018)    --

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

Nomenclature
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 [1276]. GPR84 is a structurally-unrelated G protein-coupled receptor which has been found to respond to medium chain fatty acids [2254].   [215,557,1709,1710,2173]. 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 surface 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) [159,215,216]. The GABA B1 subunit harbours the GABA (orthosteric)-binding site within an extracellular domain (ECD) venus flytrap module (VTM), whereas the GABA B2 subunit mediates G protein-coupled signalling [215,681,683,1709]. The two subunits interact by direct allosteric coupling [1485], 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 [681,1161,1709]. 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 [159,270,1709]. 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 [409,1708]. 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 [116,1907,2160] and are re-viewed by [1711]. The molecular complexity of GABAB receptors is further increased through association with trafficking and effector proteins [Schwenk et al., 2016, Nature Neuroscience 19 (2):  and reviewed by [1707]. Four isoforms of the human GABA B1 subunit have been cloned. The predominant GABA B1a 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 [1749,2216]. Only the 1a and 1b variants are identified as components of native receptors [215]. Additional GABA B1 subunit isoforms have been described in rodents and humans [1236] and reviewed by [159].  [215,634,635]. Radioligand K D values relate to binding to rat brain membranes. CGP 71872 is a photoaffinity ligand for the GABA B1 subunit [137]. CGP27492 (3-APPA), CGP35024 (3-APMPA) and CGP 44532 act as antagonists at human GABA A ρ1 receptors, with potencies in the low micromolar range [634]. 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 [650]. Synthetic positive allosteric modulators with low, or no, intrinsic activity include CGP7930, GS39783, BHF-177 [2223] and (+)-BHFF [9,159,166,634]. The site of action of CGP7930 and GS39783 appears to be on the heptahelical domain of the GABA B2 subunit [534,1709]. In the presence of CGP7930 or GS39783, CGP 35348 and 2-hydroxy-saclofen behave as partial agonists [634]. A negative allosteric modulator of GABA B activity has been reported [351]. 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 [563,2184]. A similar phenotype has been found for GABA B2 -/-BALB/c mice [669].  Galanin receptors (provisional nomenclature as recommended by NC-IUPHAR [612]) are activated by the endogenous peptides galanin (GAL, P22466) and galanin-like peptide (GALP, Q9UBC7). Human galanin (GAL, P22466) is a 30 amino-acid non-amidated peptide [579]; 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.

Comments:
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 [1321]. 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 [608,1982,1996,1997,2258]. 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 [758,2342]. 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 [ [608,1996,1997]. 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 [1847].

Ghrelin receptor G protein-coupled receptors → Ghrelin receptor
Overview: The ghrelin receptor (nomenclature as agreed by the NC-IUPHAR Subcommittee for the Ghrelin receptor [456]) 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 [1399]. Alternative splicing results in the formation of a second peptide, [des-Gln 14 ]ghrelin (GHRL, Q9UBU3) with equipotent biological activity [907]. A unique post-translational modification (octanoylation of Ser 3 , catalysed by ghrelin O-acyltransferase (MBOAT4, Q96T53) [2374] 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 [1128]. Structure activity studies showed the first five N-terminal amino acids to be the minimum required for binding [131], 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 [899]. In cell systems, the ghrelin receptor is constitutively active [900], 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 [1652].  [130], 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; [897]). 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 [622]. A number of selective antagonists have been reported, including peptidomimetic [1514] and non-peptide small molecules including GSK1614343 [1684,1848]. (GCG, P01275), glucose-dependent insulinotropic polypeptide (also known as gastric inhibitory polypeptide (GIP, P09681)), GHRH (GHRH, P01286) and secretin (SCT, P09683). One common precursor (GCG) generates glucagon (GCG, P01275), glucagon-like peptide 1 (GCG, P01275) and glucagon-like peptide 2 (GCG, P01275) peptides [952]. For a recent review on review the current understanding of the structures of GLP-1 and GLP-1R, the molecular basis of their interaction, and the signaling events associated with it, see de Graaf et al., 2016 [736].

Comments:
The glucagon receptor has been reported to interact with receptor activity modifying proteins (RAMPs), specifically RAMP2, in heterologous expression systems [384], 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 [612], also called Type I and Type II GnRH receptor, respectively [1456]) have been cloned from numerous species, most of which express two or three types of GnRH receptor [1455, 1456,1971]. 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 [1455,1456,1971] 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 [1455, 1456,1971]. 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 hormonedependent conditions [1079]. Notably, agonists cause desensitization of GnRH-stimulated gonadotropin secretion and the con-sequent reduction in circulating sex steroids is exploited to treat hormone-dependent cancers of the breast, ovary and prostate [1079]. 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 [1496]. Phylogenetic classifications divide GnRH receptors into three [1456] or five groups [2311] and highlight examples of gene loss through evolution, with humans retaining only one ancient gene.  [752] but coupling to G s and G i is evident in some systems [1157,1178]. GnRH 2 receptors may also mediate (heterotrimeric) G protein-independent signalling to protein kinases [319]. There is increasing evidence for expression of GnRH receptors on hormone-dependent cancer cells where they can exert antiproliferative and/or proapoptotic effects and mediate effects of cytotoxins conjugated to GnRH analogues [357, 814,1284,1885].
In some human cancer cell models GnRH II (GNRH2, O43555) is more potent than GnRH I (GNRH1, P01148), implying mediation by GnRH 2 receptors [757], but GnRH 2 receptors are not expressed by humans because the human GNRHR2 gene contains a frame shift and internal stop codon [1496]. The possibility remains that this gene generates GnRH 2 receptor-related proteins (other than the full-length receptor) that mediate responses to GnRH II (GNRH2, O43555) (see [1560]). Alternatively, evidence for multiple active GnRH receptor conformations [319,320,597,1407,1456] raises the possibility that GnRH 1 receptor-mediated proliferation inhibition in hormone-dependent cancer cells is dependent upon a conformation that couples to G i rather than G q/11 proteins as in pituitary cells [320,1407]. Loss-of-function mutations in the GnRH 1 receptor and deficiency of GnRH I (GNRH1, P01148) are associated with hypogonadotropic hypogonadism although some 'loss of function' mutations may actually prevent trafficking of 'functional' GnRH 1 receptors to the cell surface, as evidenced by recovery of function by nonpeptide antagonists [1230]. Human GnRH 1 receptors are poorly expressed at the cell surface because of failure to meet structural quality control criteria for endoplasmic reticulum exit [598,1232], and this increases susceptibility to point mutations that further impair trafficking [598,1230]. GnRH receptor signalling may require receptor oligomerisation [412,1155].

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 [1692]. 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 [2015,2389]. See [455] for discussion.
See reviews [455] and [1961]. In addition to those shown above, further small molecule agonists have been reported [793].

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. HCA 3 has been shown to be activated by aromatic D-amino acids.  Comments: 2-acylamino-4,6-diphenylpyridine derivatives have been described and are the first small molecule kisspeptin receptor antagonists reported with potential for treatment of sex-hormone dependent diseases such as prostate cancer and endometriosis [1120] .
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 [1288] and the vanilloid TRPV1 ligand-gated nonselective cation channel [1421]. 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 [280]. Cysteinyl-leukotrienes have also been suggested to signal through the P2Y 12 receptor [625,1600,1659], GPR17 [395] and GPR99 [1036].  [280]) is activated by the endogenous lipidderived, anti-inflammatory ligands lipoxin A 4 (LXA 4 ) and 15-epi-LXA 4 (aspirin triggered lipoxin A4, ATL). The FPR2/ALX receptor also interacts with endogenous peptide and protein ligands, such as MHC binding peptide [365] as well as annexin I (ANXA1, P04083) (ANXA1) and its N-terminal peptides [415,1688]. 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 [1788]. Furthermore, FPR2/ALX has been suggested to act as a receptor mediating the proinflammatory actions of the acute-phase reactant, serum amyloid A [2002,2047]. The agonist activity of the lipid mediators described has been questioned [804,1716], which may derive from batchto-batch differences, partial agonism or biased agonism. Results from Cooray et al. (2013) [415] 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 [64,1343,1818]. Note that the data for FPR2/ALX are also reproduced on the Formylpeptide receptor pages.

Oxoeicosanoid receptors (OXE, nomenclature agreed by the NC-IUPHAR subcommittee on Oxoeicosanoid Receptors
[236]) 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 [908].  [378]. 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, LPA-induced phenomena in the literature, indicating that a majority of LPA-dependent phenomena are receptor-mediated. Binding affinities of unlabeled, natural LPA and AEAp to LPA 1 were measured using backscattering interferometry (pK d = 9) [1466]. Binding affinities were 77-fold lower than than values obtained using radioactivity [2371]. Targeted deletion of LPA receptors has clarified signalling pathways and identified physiological and pathophysiological roles. Independent validation 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 [949]. LPA has also been described as an agonist for the transient receptor potential (Trp) ion channel TRPV1 [1586] and TRPA1 [1111]. LPA was originally proposed to be a ligand for GPCR35, but data show that in fact it is a receptor for CXCL17 (CXCL17, Q6UXB2) [1379]. All of these proposed non-GPCR receptor identities require confirmation and are not currently recognized as bona fide LPA receptors. There is growing evidence for in vivo efficacy of these chemical antagonists in several disorders, including fetal hydrocephalus [2408], fetal hypoxia [857], lung fibrosis [1618], systemic sclerosis [1618] and atherosclerosis progression [1154]. The LPA 2 selective agonist, GRI977143, also shows efficacy in an animal model of multiple sclerosis [1896]. The LPA 5 selective antagonist, AS2717638, is effective in pain models [1058].

Further reading on Lysophospholipid (LPA) receptors
Chun J et al. (2010)  tems, targeted deletion of the different S1PRs, and most recently, mouse models that report in vivo S1P1R activation [1134,1135]. A crystal structure of an S1P 1 -T4 fusion protein confirmed aspects of ligand binding, specificity, and receptor activation determined previously through biochemical and genetic studies [172,805]. Fingolimod (FTY720), the first drug to target any of the lysophospholipid receptors, binds to four of the five S1PRs, and was the first oral therapy for multiple sclerosis [390]. The mechanisms of action of fingolimod and other S1PR modulating drugs in development include binding S1PRs in multiple organ systems, e.g., immune and nervous systems, although the precise nature of their receptor interactions requires clarification [405,753,754,1739].

Comments:
The FDA-approved immunomodulator fingolimod (FTY720) is phosphorylated in vivo [33] to generate an agonist with activity at S1P 1 , S1P 3 , S1P 4 and S1P 5 receptors [237,1371]. Many of the physiological consequences of fingolimod-phosphate ad-ministration, as well as those of other currently described S1P 1 agonists, may involve functional antagonism via ubiquitination and subsequent degradation of S1P 1 [1637]. Additionally, receptor specificities of the different compounds may depend on the functional assay system utilized and from which species the receptor sequence originated.
The MT 3 binding site of hamster brain and peripheral tissues such as kidney and testis, also termed the ML 2 receptor, binds selec-  P16083 [1601, 1602]). The MT 3 binding site activated by 5MCA-NAT in eye ciliary body is positively coupled to adenylyl cyclase and regulates chloride secretion [928]. 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 [530] although melatonin does not bind to GPR50 receptors. Several variants of the MTNR1B gene have been associated with increased type 2 diabetes risk [1043].

Further reading on Melatonin receptors
Cecon E et al.   [1899]) are a family of G protein-coupled receptors activated by the neurotransmitter glutamate. The mGlu family is composed of eight members (named mGlu1 to mGlu8) which are divided in three groups based on similarities of agonist pharmacology, primary sequence and G protein coupling to effector: Group-I (mGlu 1 and mGlu 5 ), Group-II (mGlu 2 and mGlu 3 ) and Group-III (mGlu 4 , mGlu 6 , mGlu 7 and mGlu 8 ) (see Further reading).
Structurally, mGlu are composed of three juxtaposed domains: a core G protein-activating seven-transmembrane domain (TM), common to all GPCRs, is linked via a rigid cysteine-rich domain (CRD) to the Venus Flytrap domain (VFTD), a large bi-lobed extracellular domain where glutamate binds. The structures of the VFTD of mGlu 1 , mGlu 2 , mGlu 3 , mGlu 5 and mGlu 7 have been solved [1177,1482,1530,2156]. 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 [383,515,2335]. mGlu form constitutive dimers crosslinked by a disulfide bridge. Recent studies revealed the possible formation of heterodimers between either group-I receptors, or within and between group-II and -III receptors [518]. Although well characterized in transfected cells, co-localization and specific pharmacological properties also suggest the existence of such heterodimers in the brain [1493,2393].
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 ac-tivated by 3,5-DHPG and (S)-3HPG [221] and antagonized by (S)-hexylhomoibotenic acid [1346]. Group-II mGlu receptors may be activated by LY389795 [1483], LY379268 [1483], eglumegad [1898 2337], DCG-IV and (2R,3R)-APDC [1899, and antagonised by eGlu [979] and LY307452 [571,2289]. Group-III mGlu receptors may be activated by L-AP4 and (R,S)-4-PPG [666]. 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 [1099]. 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. PCCG-4 (pIC 50  Comments: The activity of NAAG as an agonist at mGlu 3 receptors was questioned on the basis of contamination with glutamate [374,631], but this has been refuted [1553].  [1008,1906]). 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 and may have unappreciated biased or neutral activity at other subtypes [849]. Potential 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 [2183], and is an antagonist at all Group-III mGluRs with an IC 50 of 30μM. A potential novel metabotropic glutamate receptor coupled to phospho-inositide turnover has been observed in rat brain; it is activated by 4-methylhomoibotenic acid (ineffective as an agonist at recombinant Group I metabotropic glutamate receptors), but is resistant to LY341495 [392]. 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 [1112,1675] 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.  (MLN, P12872), a 22 amino-acid peptide derived from a precursor (MLN, P12872), 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. 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 [834,2085,2117]. However, differences between the N-terminus regions of these receptors means that their cognate peptide ligands do not readily activate each other [448,1863]. In laboratory rodents, the gene encoding the motilin percursor appears to be absent, while the receptor appears to be a pseudogene [834,1861]. 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 [1424,1587]. 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 [1269]. Marked differences in ligand affinities for the motilin receptor in dogs and humans may be explained by significant differences in receptor structure [1862]. 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; [2430]). Small molecule motilin receptor agonists are now described [1269, 1863,2293]. The motilin receptor does not appear to have constitutive activity [897]. Although not proven, the existence of biased agonism at the receptor has been suggested [1402,1462,1860]. A truncated 5-transmembrane structure has been identified but this is without activity when transfected into a host cell [588]. Receptor dimerisation has not been reported.  P48645) showing a broad tissue distribution, but which is expressed at highest lev-els in the upper gastrointestinal tract, CNS, bone marrow and fetal liver. Much shorter versions of NmU are found in some species, but not in human, and are derived at least in some instances from the proteolytic cleavage of the longer NmU. Despite species differences in NmU structure, the C-terminal region (particularly the C-terminal pentapeptide) is highly conserved and contains biological activity. Neuromedin S (neuromedin S-33 (NMS, Q5H8A3)) has also been identified as an endogenous agonist [1497]. 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.  Endogenous agonists neuropeptide FF (NPFF, O15130) [728,729,1476], RFRP-3 (NPVF, Q9HCQ7) [729,730,1476] neuropeptide FF (NPFF, O15130) [729,1475] Selective agonists -dNPA [1829], AC263093 [1194] Antagonists RF9 (pK i 7. Comments: An orphan receptor GPR83 (Q9NYM4) shows sequence similarities with NPFF1, NPFF2, PrRP and QRFP receptors. The antagonist RF9 is selective for NPFF receptors, but does not distinguish between the NPFF1 and NPFF2 subtypes (pK i 7.1 and 7.2, respectively, [1974]).

Further reading on Neuropeptide FF/neuropeptide AF receptors
Moulédous L et al.  and several splice variants have been identified in the human NPS receptor. The most interesting of these is an Asn-Ile exchange at position 107 (Asn 107 Ile). The human NPS receptor Asn 107 Ile dis-played similar binding affinity but higher NPS potency (by approx. 10-fold) than human NPS receptor Asn107 [1787]. Several epidemiological studies reported an association between Asn 107 Ile receptor variant and susceptibility to panic disorders [507,510,1629,1758]. The SNP Asn 107 Ile has also been linked to sleep behavior [727], inflammatory bowel disease [440], schizophrenia [1254], increased impulsivity and ADHD symptoms [1186]. Interestingly, a carboxy-terminal splice variant of human NPS receptor was found to be overexpressed in asthmatic patients [1193].   [612]) is activated by two 23amino-acid peptides, neuropeptide W (neuropeptide W-23 (NPW, Q8N729)) and neuropeptide B (neuropeptide B-23 (NPB, Q8NG41)) [638,1953]. C-terminally extended forms of the peptides (neuropeptide W-30 (NPW, Q8N729) and neuropeptide B-29 (NPB, Q8NG41)) also activate NPBW1 [233]. 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 [233].  [1953] Comments: Potency measurements were conducted with heterologously-expressed receptors with a range of 0.14-0.57 nM (NPBW1) and 0.98-21 nM (NPBW2).

Nomenclature
NPBW1 -/mice show changes in social behavior, suggesting that the NPBW1 pathway may have an important role in the emotional responses of social interaction [1537].
For a review of the contribution of neuropeptide B/W to social dominance, see Watanabe and Yamamoto, 2015 [2270]. 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 [1512].
Two antagonists have been discovered and reported to have affin-ity for NPBW1, ML181 and ML250, the latter exhibiting improved selectivity (100 fold) for NPBW1 compared to MCH1 receptors [762,763]. Computational insights into the binding of antagonists to this receptor have also been described [1667].   [1444]) 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, [1310]). 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 [743]. 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 [566]. 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. [ [691]. NPY-(13-36) is Y 2 selective relative to Y 1 and Y 5 receptors. PYY-(3-36) is Y 2 selective relative to Y 1 receptors. Note that Pro34-containing NPY and PYY can also bind Y 4 and Y 5 , thus they are selective only relative to Y 2 . The y 6 receptor is a pseudogene in humans, but is functional in mouse, rabbit and some other mammals.

Further reading on Neuropeptide Y receptors
Bowers ME et al. (2012)  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 [1585]. It has been reported to interact with the NTS 1 receptor [1388] and the NTS 2 receptor [283], 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 [211] and later in rat [1689].
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 [1613] and the identification of biased signalling by opioid receptor ligands, in particular, compounds previously characterized as antagonists [255]. Pathway bias for agonists makes general rank orders of potency and efficacy somewhat obsolete, so these do not appear in the table. 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 [267,268]. Negative allosteric modulation of opioid receptors has been previously suggested [1048], whether all compounds are acting at a similar site remains to be established.  [1168,1747,1852] 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 cells also stress the importance of G q/11 [1167]. Coupling of both receptors to G i/o and G s has also been reported [1046,1170,1255,1769]. For most native cellular responses observed, the G protein pathway is unknown. The relative potency order of endogenous ligands depends on the cellular signal transduction machinery [1166]. Similarly, [Ala 11 [293] and Rhodamine Green-orexin-A [445] are also useful radioligand tools. Orexin receptors have been reported to be able to form complexes with each other and some other GPCRs as well as σ 1 receptors, which might affect the signaling and pharmacology [1169,1549]. Loss-of-function mutations in the gene encoding the OX 2 receptor underlie canine hereditary narcolepsy [1287]. Antagonists of the orexin receptors are the focus of major drug discovery efforts for their potential to treat insomnia and other disorders of wakefulness [1816], while agonists would likely be useful in human narcolepsy.  [1,2]) are activated by the endogenous ligands ATP, ADP, uridine triphosphate, uridine diphosphate and UDP-glucose. The relationship of many of the cloned receptors to endogenously ex-pressed receptors is not yet established and so it might be appropriate to use wording such as 'uridine triphosphate-preferring (or ATP-, etc.) P2Y receptor' or 'P2Y 1 -like', etc., until further, as yet undefined, corroborative criteria can be applied [271,567,966,2227,2281].
Clinically used drugs acting on these receptors include the dinucleoside polyphosphate diquafosol, agonist of the P2Y 2 receptor subtype, approved in Japan for the management of dry eye disease [1207], and the P2Y 12 receptor antagonists prasugrel, ticagrelor and cangrelor, all approved as antiplatelet drugs [298,1734]. Comments: A series of 4-alkyloxyimino derivatives of uridine-5'-triphosphate which could be useful for derivatization as fluorescent P2Y 2/4/6 receptor probes has been recently synthesized [986].

Nomenclature
Single nucleotide polymorphisms of the P2YR 1 gene have been associated to different platelet reactivity to ADP ADP [863]. Three frequent nonsynonymous P2Y 2 receptor polymorphisms have been identified, one of which was significantly more common in cystic fibrosis patients. This polymorphism is linked to increases in Ca 2+ influx in transfected cells, and might therefore play a role in disease development [286]. Although uridine triphosphate (UTP) was also shown to be a biased agonist at P2Y 11 , this is still under debate [1508,2297]. A group of single nucleotide polymorphisms in the P2Y 12 gene, forming the so called P2Y 12 H2 haplotype, has been associated with increased platelet responsiveness to ADP, increased risk of peripheral arterial disease and with coronary artery disease [321]. The platelet-type bleeding disorder due to P2Y 12 receptor defects is an autosomal recessive condition characterized by mild to moderate mucocutaneous bleeding and excessive bleeding after surgery or trauma. The defect is due to the inability of ADP to induce platelet aggregation [317]. The P2Y 13 receptor Met-158-Thr polymorphism, which is in linkage disequilibrium with the P2Y 12 locus, is not associated with acute myocardial infarction, diabetes mellitus or related risk factors [47]. The P2Y 14 receptor was previously considered to exclusively bind sugar nucleotides such as UDP-glucose and UDP-galactose [331]. However, more recent evidence with several cell lines has demonstrated that uridine diphosphate (UDP) is 5-fold more potent than UDP-glucose [311]. UDP was also shown to competitively antagonise the UDP-glucose response at the human recombinant P2Y 14 receptor [632]. Platelet-activating factor receptor G protein-coupled receptors → Platelet-activating factor receptor Overview: Platelet-activating factor (PAF, 1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine) is an ether phospholipid mediator associated with platelet coagulation, but also subserves inflammatory roles. The PAF receptor (provisional nomenclature recommended by NC-IUPHAR [612]) is activated by PAF and other suggested endogenous ligands are oxidized phosphatidylcholine [1378] and lysophosphatidylcholine [1615]. It may also be activated by bacterial lipopolysaccharide [1540].

Nomenclature
The EP 1 agonist 17-phenyl-ω-trinor-PGE 2 also shows agonist activity at EP 3 and EP 4 receptors [617,2113]. Butaprost and SC46275 may require de-esterification within tissues to attain full agonist potency. There is evidence for subtypes of FP [1281] and TP receptors [1151,1779]. mRNA for the EP 3 receptor undergoes alternative splicing to produce variants which can interfere with signalling [1632] or generate complex patterns of G-protein (G i/o , G q/11 , G s and G 12,13 ) coupling (e.g. [1143,1557]). The number of EP 3 receptor (protein) variants are variable depending on species, with five in human, three in rat and three in mouse. Putative receptor(s) for prostamide F (which as yet lack molecular correlates) and which preferentially recognize PGF2-1-ethanolamide and its analogues (e.g. Bimatoprost) have been identified, together with moderate-potency antagonists (e.g. AGN 211334) [2328].
The free acid form of AL-12182, AL12180, used in in vitro studies, has a EC 50 of 15nM which is the concentration of the compound giving half-maximal stimulation of inositol phosphate turnover in HEK-293 cells expressing the human FP receptor [1941].

References given alongside the TP receptor agonists I-BOP [1409]
and STA 2 [69] use human platelets as the source of TP receptors for competition radio-ligand binding assays to determine the indicated activity values.
Pharmacological evidence for a second IP receptor, denoted IP 2 , in the central nervous system [2091,2272] and in the BEAS-2B human airway epithelial cell line [2317] [894]) are unique members of the GPCR superfamily activated by proteolytic cleavage of their amino terminal exodomains. Agonist proteinase-induced hydrolysis unmasks a tethered ligand (TL) at the exposed amino terminus, which acts intramolecularly at the binding site in the body of the receptor to effect transmembrane signalling. TL sequences at human PAR1-4 are SFLLRN-NH 2 , SLIGKV-NH 2 , TFRGAP-NH 2 and GYPGQV-NH 2 , respectively. With the exception of PAR3, synthetic peptides with these sequences (as carboxyl terminal amides) are able to act as agonists at their respective receptors. Several proteinases, including neutrophil elastase, cathepsin G and chymotrypsin can have inhibitory effects at PAR1 and PAR2 such that they cleave the exodomain of the receptor without inducing activation of Gαq-coupled calcium signalling, thereby preventing activation by activating proteinases but not by agonist peptides. Neutrophil elastase (NE) cleavage of PAR1 and PAR2 can however activate MAP kinase signaling by exposing a TL that is different from the one revealed by trypsin [1764] [120,785]) may be divided into two pairs, RXFP1/2 and RXFP3/4. Endogenous agonists at these receptors are heterodimeric peptide hormones structurally related to insulin: relaxin-1 (RLN1, P04808), relaxin (RLN2, P04090), relaxin-3 (RLN3, Q8WXF3) (also known as INSL7), insulin-like peptide 3 (INSL3 (INSL3, P51460)) and INSL5 (INSL5, Q9Y5Q6). Species homologues of relaxin have distinct pharmacology and relaxin (RLN2, P04090) interacts with RXFP1, RXFP2 and RXFP3, whereas mouse and rat relaxin selectively bind to and activate RXFP1 [1912]. Relaxin-3 (RLN3, Q8WXF3) is the ligand for RXFP3 but it also binds to RXFP1 and RXFP4 and has differential affinity for RXFP2 between species [1911]. INSL5 (INSL5, Q9Y5Q6) is the ligand for RXFP4 but is a weak antagonist of RXFP3. Relaxin (RLN2, P04090) and INSL3 (INSL3, P51460) have multiple complex binding interactions with RXFP1 [1930] and RXFP2 [886] which direct the N-terminal LDLa modules of the receptors together with a linker domain to act as a tethered ligand to direct receptor signaling [1913]. INSL5 [1435]. Relaxin has vasodilatory, anti-fibrotic, angiogenic, anti-apoptotic and anti-inflammatory effects. A small molecule allosteric agonists ML290 has been developed [1944,2349], and a relaxin B-chain mimetic peptide B7-33 has been developed which that has cell specific signaling properties [911]. The antifibrotic actions of relaxin are dependent on the angiotensin receptor AT 2 [377]. INSL3 (INSL3, P51460) is the cognate peptide for RXFP2 and is a circulating hormone that in males is essential for testicular descent in utero [1556] and in females has important roles in ovarian follicle function [961]. In adults, INSL3 has potential roles in testicular function [962] and the musculoskeletal system [472]. RXFP2 is also present in brain, associated with cortico-thalamic motor circuits [1917]. cAMP elevation is the major signalling pathway for both RXFP1 and RXFP2 [919,920], but RXFP1 also activates MAP kinases, nitric oxide signalling, and tyrosine kinase phosphorylation; and relaxin can interact with glucocorticoid receptors [787]. Receptor expression profiles suggest that RXFP3 is a brain neuropeptide receptor and RXFP4 a gut hormone receptor. The brain relaxin-3/RXFP3 system modulates feeding [652,653,823,1934,1992] via effects in hypothalamus [475,652,1039], anxiety [1842, 2415], reward and motivated, goal-directed behaviours [906,1842,2239], and spatial and so-cial memory [34,780]. Of the other relaxin peptides, relaxin-3 (RLN3, Q8WXF3) is an agonist at RXFP3 and RXFP4 whereas INSL5 (INSL5, Q9Y5Q6) is an agonist at RXFP4 and a weak antagonist at RXFP3. INSL5 (INSL5, Q9Y5Q6) is secreted from enteroendocrine L cells and the INSL5/RXFP4 system affects food intake [751] and glucose homeostasis [1331]. RXFP3 and RXFP4 couple to G i/o and inhibit adenylyl cyclase [1296,2191], and also cause Erk1/2 phosphorylation [2191]. RXFP4 also causes phosphorylation of p38MAPK, Akt and S6RP [55] and GLP-1 secretion in vitro [54]. There is evidence that at RXFP3, relaxin (RLN2, P04090) is a biased ligand compared to the cognate ligand relaxin-3 (RLN3, Q8WXF3) [2191].

Somatostatin receptors G protein-coupled receptors → Somatostatin receptors
Overview: Somatostatin (somatotropin release inhibiting factor) is an abundant neuropeptide, which acts on five subtypes of somatostatin receptor (SST 1 -SST 5 ; nomenclature as agreed by the NC-IUPHAR Subcommittee on Somatostatin Receptors [773]). Activation of these receptors produces a wide range of physiological effects throughout the body including the inhibition of secretion of many hormones. Endogenous ligands for these receptors are somatostatin-14 (SRIF-14 (SST, P61278)) and somatostatin-28 (SRIF-28 (SST, P61278)). Cortistatin-14 {Mouse, Rat} has also been suggested to be an endogenous ligand for somatostatin receptors [468]. Agonists pasireotide [1893] pasireotide [1893], veldoreotide [15] pasireotide [1893] NNC269100 [1306], veldoreotide [15] pasireotide [1893], veldoreotide [15] Selective agonists L-797,591 [1817], Des-Ala Overview: Nomenclature as recommended by NC-IUPHAR [455]. The Succinate receptor has been identified as being activated by physiological levels of the Kreb's 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, inflammation or immune response.

Further reading on Succinate receptor
Ariza AC et al. (2012) The succinate receptor as a novel therapeutic target for oxidative and metabolic stress-related conditions.

Tachykinin receptors G protein-coupled receptors → Tachykinin receptors
Overview: Tachykinin receptors (provisional nomenclature as recommended by NC-IUPHAR [612]) are activated by the endogenous peptides substance P (TAC1, P20366) (SP), neurokinin A (TAC1, P20366) (NKA; previously known as substance K, neurokinin α, neuromedin L), neurokinin B (TAC3, Q9UHF0) (NKB; previously known as neurokinin β, neuromedin K), neuropeptide K (TAC1, P20366) and neuropeptide γ (TAC1, P20366) (N-terminally extended forms of neurokinin A). The neurokinins (A and B) are mammalian members of the tachykinin family, which includes peptides of mammalian and nonmammalian origin containing the consensus sequence: Phe-x-Gly-Leu-Met. Marked species differences in in vitro pharmacology exist for all three receptors, in the context of nonpeptide ligands. Antagonists such as aprepitant and fosaprepitant were approved by FDA and EMA, in combination with other antiemetic agents, for the prevention of nausea and vomiting associated with emetogenic cancer chemotherapy.

Comments:
The NK 1 receptor has also been described to couple to G proteins other than G q/11 [1828]. The crystal structure of the human NK 1 receptor in complex with antagonists has been determined [1909,2391]. The hexapeptide agonist sep-tide appears to bind to an overlapping but non-identical site to substance P (TAC1, P20366) on the NK 1 receptor. There are additional subtypes of tachykinin receptor; an orphan receptor (Swis-sProt P30098) with structural similarities to the NK 3 receptor was found to respond to NKB when expressed in Xenopus oocytes or Chinese hamster ovary cells [509,1150]. Trace amine receptor G protein-coupled receptors → Trace amine receptor Overview: Trace amine-associated receptors were discovered from a search for novel 5-HT receptors [205], where 15 mammalian orthologues were identified and divided into two families. The TA 1 receptor (nomenclature as agreed by the NC-IUPHAR Subcommittee for the Trace amine receptor [1355]) has affinity for the endogenous trace amines tyramine, β-phenylethylamine and octopamine in addition to the classical amine dopamine [205]. Emerging evidence suggests that TA 1 is a modulator of monoaminergic activity in the brain [2351] with TA 1 and dopamine D 2 receptors shown to form constitu-tive heterodimers when co-expressed [572]. In addition to trace amines, receptors can be activated by amphetamine-like psychostimulants, and endogenous thyronamines.
TAAR3, in some individuals, and TAAR4 are pseudogenes in man, although functional in rodents. The signalling characteristics and pharmacology of TAAR 5 (PNR, Putative Neurotransmitter Receptor: TAAR5, O14804), TAAR 6 (Trace amine receptor 4, TaR-4: TAAR6, 96RI8), TAAR 8 (Trace amine receptor 5, GPR102: TAAR8, Q969N4 ) and TAAR 9 (trace amine associated receptor 9: TAAR9, 96RI9) are lacking. The thyronamines, endogenous derivatives of thyroid hormone, have affinity for rodent cloned trace amine receptors, including TA 1 [1881]. An antagonist EPPTB has recently been described with a pK i of 9.1 at the mouse TA 1  Overview: The urotensin-II (U-II) receptor (UT, nomenclature as agreed by the NC-IUPHAR Subcommittee on the Urotensin receptor [516,612,2211]) is activated by the endogenous dodecapeptide urotensin-II (UTS2, O95399), originally isolated from the urophysis, the endocrine organ of the caudal neurosecretory system of teleost fish [150,2210]. Several structural forms of U-II exist in fish and amphibians. The goby orthologue was used to identify U-II as the cognate ligand for the pre-dicted receptor encoded by the rat gene gpr14 [425,1304,1498,1603]. Human urotensin-II (UTS2, O95399), an 11-amino-acid peptide [425], retains the cyclohexapeptide sequence of goby U-II that is thought to be important in ligand binding [240,1101]. This sequence is also conserved in the deduced amino-acid sequence of rat urotensin-II {Rat} (14 amino-acids) and mouse urotensin-II {Mouse} (14 amino-acids), although the N-terminal is more divergent from the human sequence [424]. A second endogenous ligand for the UT has been discovered in rat [2053]. This is the urotensin II-related peptide (UTS2B, Q765I0), an octapeptide that is derived from a different gene, but shares the C-terminal sequence (CFWKYCV) common to U-II from other species. Identical sequences to rat urotensin II-related peptide (UTS2B, Q765I0) are predicted for the mature mouse and human peptides [523]. UT exhibits relatively high sequence identity with somatostatin, opioid and galanin receptors [2211].

Further reading on VIP and PACAP receptors
Harmar