Class A Orphans: Introduction

The sequencing of the human genome has allowed NC-IUPHAR to catalog all of the human gene sequences potentially encoding GPCRs, excluding sensory receptors. In addition to established transmitter systems, the classification in the Guide to PHARMACOLOGY also includes ‘orphan’ GPCRs where the endogenous ligand(s) is not known. Considerable progress has been made in screening artificially expressed receptors to identify the cognate endogenous ligand. Where understanding of the physiology, pharmacology and pathology has begun to emerge, receptors have been officially classified and named (usually after the endogenous ligand following IUPHAR nomenclature conventions) and published in Pharmacological Reviews (Publications). Physiological functions have now been assigned to a number of receptors previously designated as orphans. These include the family of free fatty acid receptors (FFA1, FFA2 and FFA3, [84]); neuropeptide B and W as ligands of NPBW1 (GPR7) and NPBW2 (GPR8) [82]; the protein encoded by the APJ gene [27], now classified as the apelin receptor [77]; GPR30 as the estrogen G protein-coupled receptor (GPER: [67,78,80,87,94]); GPR54 as the kisspeptin receptor [35]; GHS-R1a as the ghrelin receptor [17]; the TA1 receptor activated by endogenous trace amine ligands, including tyramine and β-phenylethylamine [54] and GPR131 as the bile acid receptor (GPBA: [57]).

A recent update review published by NC-IUPHAR has extended the number of receptors where the criteria for deorphanisation has been met, particularly where replicated by independent groups (see Davenport et al., 2013 [16]; full details of the criteria for deorphanisation are also contained in this review). The following recommendations are made for new receptor names based on eleven pairings for class A GPCRs: Hydroxycarboxylic acid receptors, HCA1 (GPR81) with lactate; HCA2 (GPR109A) with 3-hydroxy-butyric acid; HCA3 (GPR109B) with 3-hydroxy octanoic acid [70]; lysophosphatidic acid receptors, LPA4 (GPR23) [42,69,85], LPA5 (GPR92) [36,41,46,97], LPA6 (p2y5) [75,100]; Free Fatty Acid receptors, FFA4 (GPR120) with Omega-3 fatty acids [10,23,25]; chemerin receptor (CMKLR1, ChemR23) with chemerin [49,60,101]; CXCR7 (CMKOR1, and recently renamed to ACKR3 by the NC-IUPHAR subcommittee for the chemokine receptors) with chemokines CXCL12 (SDF-1) and CXCL11 (ITAC) [4,9,79]; succinate receptor (SUCNR1) with succinate [22,83]; oxoglutarate receptor OXGR1 with 2-oxoglutarate [22,83]. Pairings have been highlighted for a further thirty receptors in Class A where further input is needed from the scientific community to validate these findings. Details of these pairings with cognate ligands reported by a single paper or where a formal pairing is yet to be agreed can be found in Davenport et al., 2013 [16]. Fifty-seven human Class A receptors (excluding pseudogenes) are still considered orphans; information is provided where there is a significant phenotype in genetically modified animals (see table below).

To reflect the dynamic nature of the field, where a single paper exists describing a new pairing, a list is maintained on the Guide to PHARMACOLOGY (Latest Pairings List). Occasionally reported pairings are retracted and these are also recorded here. Most, if not all, human orphan receptors have now been expressed in cell lines but despite intense effort particularly by the pharmaceutical industry, there is no public information about the cognate ligand for a significant number of them. It is possible that the remaining receptors may function without ligands by being constitutively active or by modulating the activity of other GPCRs for example by dimerization [20,43]. It is clear from knockout studies in mice and genetic deletions in man that these receptors may have a physiological or pathophysiological role and can still be exploited as drug targets in the absence of an identifiable ligand.

For a recent review on orphan GPCR deorphanizations please see Davenport et al., 2013 [16].

Gene name K/O mouse Y/NPhenotype Y/NPhenotype descriptionReference
BB3YesYesObesity, hypertension, impaired insulin metabolism[68,71]
BB3YesYesHyperphagia, reduced metabolic rate[2]
BB3YesYesOverexpression of melanin concentrating hormone receptors[53]
GPR3YesYesPremature ovarian aging, premature termination of meiotic arrest in oocytes[40,61]
GPR3YesYesLow basal intracellualar cAMP levels; increased stress levels [90]
GPR4YesYesMetabolic acidosis[86]
GPR4YesYesReduced tumour growth and pathological angiogenesis[98]
GPR6YesYesReduced striatal cAMP production[47]
GPR12YesYesDyslipidemia, higher body weight and fat mass [7]
GPR17YesYesEarly onset of oligodendrocyte myelination[12]
GPR17YesYesIncreased susceptibility to pulmonary inflammation [52]
GPR21YesYesResistance to diet-induced obesity, increase in glucose tolerance and insulin sensitivity, modest lean phenotype[19,73]
GPR21YesYesProtection from obesity-induced inflammation and insulin resistance, reduced macrophage infiltration into adipose tissue and liver [73]
GPR22YesYes Increased response to aortic banding including decreased fractional shortening and decompensated heart failure.[1]
GPR26YesYesIncreased anxiety and depression-like behaviours [102]
GPR34YesYesAltered immune response in hypersensitivity tests[45]
GPR37YesYesReduced striatal dopamine levels, enhanced amphetamine sensitivity, reduced motor activity and coordination and increased percentage of body fat in females.[26,56]
GPR37YesYesLower lever of endoplasmic reticulum-associated protein degradation (ERAD) and autophagic markers.[55]
GPR37L1YesYesHigh blood pressure and a high heart weight to body weight ratio [62]
GPR39YesYesAcceleration of gastric emptying, higher body weight and fat composition and increased cholesterol levels [63]
GPR39YesYesImpaired glucose tolerance, decreased insulin response to glucose [24,89]
GPR50YesYesLow body weight, partial resistance to diet induced obesity[28]
GPR50YesYesDecreased thermogenesis[5]
GPR55YesYesIncreased bone volume, impaired osteoclast function in male mice [3,96]
GPR65YesYesThermocytes and splenocytes are insensitive to pH-regulated cAMP production [37,72]
GPR68YesYesReduced osteoblast levels and decreased melanoma cell tumorigenesis [44]
GPR68YesYesUpregulated expression of Pyk2 and an increase in socdium-hydrogen antiporter activity[64]
GPR68YesYesEnhanced SPC-activation of ERK1/2[6]
GPR82YesYesLower body weight and fat content than wild type, higher insulin sensitivity and glucose tolerance and decreased serum triglycerides[18]
GPR84YesYesIncreased interleukin (Il-4, IL-5, IL-13) production by Th2 effector cells; increased IL-4 production from T cells treated with anti-CD3[91]
GPR85YesYesIncreased brain weight, enhanced neuronal survival in dendrate gyrus, and enhanced ability to discriminate spatial relationships[11,58]
GPR88YesYesHigher basal striatal phosphorylated DARPP-21-Thr-34 and lower basal dopamine[48]
GPR119YesYesLow body weight and low post-prandial levels of GLP-1 [38]
GPR132YesYesMildly cholestatic phenotype with altered hepatobiliary homeostasis and gall stone formation[30]
GPR132YesYesIncrease in IL-6 and MCP-1 production and a dramatic increase in nuclear localization of the p65 subunit of nuclear factor κB. Proinflammatory signaling and increased monocyte/endothelial interactions in the aortic wall[8]
GPR132YesYesReduced atherosclerotic plaque stability[74]
GPR132YesYesProgressive wasting syndrome in mice > 1 year. Secondary lymphoid organ enlargement associated with lymphocytic infiltration [39]
GPR183YesYesAbolished migration of bone-marrow-derived dendritic cells towards 7alpha, 25-dihydroxycholesterol[21]
GPR183YesYesReduction in the early antibody response to a T-dependent antigen[33,76]
GPR183YesYesFailure of B-cells to migrate to the outer follicle [33,76]
LGR4YesYesEmbryonic and perinatal lethality[59]
LGR4YesYesDelay in osteoblast differentiation and mineralization[51]
LGR4YesYesImpaired eye development [15]
LGR4YesYesReduced keratinocyte and epithelial cell proliferation[29,32,95]
LGR4YesYesRenal hypoplasia[31,65]
LGR5YesYesNeonatal lethality resulting from ankyloglossia, gastrointestinal distension, cyanosis and respiratory failure.[66]
MAS1YesYesElevated blood pressure and impaired endothelial function[99]
MAS1YesYesIncreased duration of long term potentiation in the dentate gyrus, increased anxiety and alterations in the onset of depotentiation[92]
MAS1YesYesErectile dysfunction [14]
MAS1YesYesIncreased sympathetic tone [93]
MRGPRDYesYesDecreased sensitivity to mechanical, cold, and heat stimuli on a congenic C57BL/6 background 
MRGPREYesYesDeletion of MRGPRE increases MRGPRF expression in the spinal cord[13]
OPN4YesYesImpaired pupillary response at high irradiances[50]
OXGR1YesYesOtitis media with effusion resulting from histopathological changes in the middle ear epithelium[34]
SUCNR1 (GPR91)YesYesImpaired renin release from the kidney in response to high glucose levels [88]
SUCNR1 (GPR91)YesYesAbolished induction of hypertension by succinate [22]
SUCNR1 (GPR91)YesYesImpaired dendritic cell migration, decreased T- cell proliferation and diminished succinate-mediated immune responses[81]


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