Orphan GPCR Family Subtypes and Products

What Are Orphan Receptors?

Orphan receptors are a family of G protein-coupled receptors (GPCRs) comprised of proteins whose endogenous ligands are not known. Once the endogenous ligand is discovered, the receptor is de-orphanized.

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Orphan Receptor Information

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GPR3

GPR6

GPR15

GPR34

GPR35

GPR37L1

GPR45

GPR50

GPR52

GPR85

GPR88

GPR142

GPR151

GPRC5A

MRGX1

MRGX2

MAS1

GPR3 cDNA was first isolate from a rat insulinoma cell line and a human neuroblastoma cDNA library. It expresses in low abundance predominantly in the central nervous system and at low levels in lung and kidney. GPR3 is involved in maintaining meiotic arrest in mammalian oocytes. Oocytes from GPR3 knockout mice resumed meiosis within antral follicles, independently of an increase in luteinizing hormone. In GPR3-null mice, progressive reduction in litter size was observed. Aging GPR3-null mice had severe reduction of fertility, manifested by an increasing number of nondeveloping early embryos upon spontaneous ovulation and massive amounts of fragmented oocytes after superovulation. Based on the above evidence, it was concluded that GPR3 plays a role in the protection or rescue of oocytes from aging.

G-protein coupled receptor 6 (GPR6) is mostly expressed in the basal ganglia’s striatopallidal neurons. GPR6 is an orphan G-protein coupled receptor that has a ubiquitous function and generates an increase in intracellular cAMP levels when it is linked to a stimulatory Gs-protein. GPR6 receptor, with highly restricted expression in dopamine receptor D2-type medium spiny neurons (MSNs) of the indirect pathway triggers interest of researchers as a novel non-dopaminergic drug target for Parkinson’s disease. Recently it was hypothesized that inhibition of GPR6 and D2 receptors coexpressed in the indirect pathway D2-type MSN antagonized each other with respect to cAMP modulation. 

GPR15 is a class A orphan G protein-coupled receptor found in epithelial cells, synovial macrophages, endothelial cells and lymphocytes especially T cells. Studies have accumulated evidence that GPR15 may modulate chronic inflammation. Findings also have implicated GPR15 for potential therapeutic intervention.

GPR34 is an orphan G protein coupled receptor, belongs to P2Y receptor family. It is a potent mediator of lysophospholipid and expressed in various tissues including stomach Mast cells, placenta, spleen, thymus, ovary, Heart, brain etc. GPR34 receptor is responsible for enhancing the antigen induced degranulation of mast cells.

GPR35 is an orphan receptor and expressed in various tissues including stomach, gastrointestinal tissues, and several types of immune cells. Up- regulation of GPR35 has been found in human mast cells upon stimulation with IgE antibodies, human macrophages treated with the environmental contaminant polycyclic aromatic hydrocarbon benzo[a]pyrene, failing heart cells, and gastric cancer cells. Known agonists of the orphan receptor GPR35 are kynurenic acid, zaprinast, 5-nitro-2-(3-phenylproplyamino) benzoic acid, and lysophosphatidic acids.

GPR37L1 (G-protein coupled receptor 37 like 1) is also known as ETBR-LP-2 (Endothelin B receptor-like protein-2) and is an orphan receptor. The receptor is strongly expressed in the human central nervous system, e.g. in cerebellar Bergmann glia, cerebral cortex, and internal capsule fibers. The fragment of this receptor is detectable in human cerebrospinal fluid.

GPR45 is an Orphan-A GPCR and an orthologue of a putative lysophosphatidic acid receptor. Its expression is found in brain: frontal cortex and caudate, but not in thalamus, hippocampus or putamen. This protein may function in the central nervous system. In addition, this expression is documented in human liver, and in mouse brain as well. 

GPR50 is a melatonin-related receptor. It does not bind melatonin and its endogenous ligand is still unknown. Nevertheless, this receptor has been shown to behave as an antagonist of melatonin receptor type 1 (MT1), which opens new pharmacological perspectives for GPR50. GPR50 was reported to inhibit MT1 melatonin receptor function through heterodimerization by abolishing high-affinity agonist binding and G protein coupling to the MT1. Data acquired from the mice lacking GPR50 implicate the receptor as an important regulator of energy metabolism. Recently GPR50 has been identified as an interacting partner of neurite outgrowth inhibitor NOGO-A to regulate neurite growth.

GPR52 is a class-A orphan G-protein-coupled receptor that can be found in human and mice, and is highly expressed in the brain and represents a promising therapeutic target for the treatment of Huntington’s disease and several psychiatric disorders. Once activated by antipsychotics reserpine, an increase of intracellular cAMP and its internalization is resulted. Members of this protein family contain transmembrane domain and may play a role in locomotor activity through modulation of dopamine, NMDA and ADORA2A-induced locomotor activity. They represent a promising therapeutic target for the treatment of Huntington’s disease and several psychiatric disorders.

GPR85 (G protein-coupled receptor 85) is also known as SREB2 (Super Conserved Receptor Expressed in Brain 2) and belongs to the family of class A (rhodopsin-like) orphan G protein-coupled receptors. The receptor is reported to be highly expressed in the brain and testis. Research has linked GPR85 to influences of brain size, behavior, and vulnerability to schizophrenia.

GPR88 is an orphan G protein-coupled receptor (GPCR) considered as a promising therapeutic target for neuropsychiatric disorders including schizophrenia, Parkinson’s disease, anxiety, and addiction. The biological effects of GPR88 activation and signal transduction pathway are still unknown due to the lack of a selective agonist appropriate for in vivo investigation.

GPR142 belongs to the family of class A (rhodopsin-like) orphan G protein-coupled receptors. Research has linked GPR142 to type 2 diabetes mellitus. GPR142 is reported to be highly expressed in pancreatic β-cells, and upon ligand binding and also in the presence of a high concentration of blood glucose, can stimulate insulin secretion. It has been hypothesized that GPR142 agonists can provide a benefit over existing type 2 diabetes therapies because of a greatly reduced risk of hypoglycemia.

The diverse physiological effects of Galanin, a biologically active neuropeptide, are mediated through cell surface G protein-coupled receptors. There are three galanin receptor subtypes, GALR1, GALR2 and GALR3 that have been widely used and Recently, a new GPCR, GalRL4 have been identified, termed as GPR151, which shows 41–43% similarity at the amino-acid level with the galanin-receptor subfamily. Galanin, widely distributed in the central and peripheral nervous systems and the endocrine systems, binds to galanin receptors to induce several regulatory functions in neuronal cells, including neuroregeneration, control of endocrine and exocrine secretions, and modulation of sensory and behavioral functions. Galanin agonists have been shown to have therapeutic application in treatment of chronic pain; galanin antagonists have therapeutic potential in treatment of Alzheimer’s disease, depression, and feeding disorders.

GPRC5A (also known as retinoic induced GPR) is a member of the type three GPR class. This protein contains seven trans-membrane domains when located within the membrane. It appears to play a role in the interaction of retinoic acid and G protein signaling pathways. Since retinoic acid is important for cellular growth and differentiation, the receptor may play a role in embryonic development and cellular differentiation within epithelial cells.

MRGX1 (MAS-related GPR member X1) is also known as SNSR4 (sensory neuron-specific G-protein-coupled receptor 4). It can be potently activated by enkephalins including BAM22 and BAM(8-22). MRGX1 receptor is expressed solely in small diameter primary sensory neurons. This restricted expression pattern is of considerable therapeutic interest because small nociceptors transmit chronic pain messages.

MRGX2 (MAS-related GPR member X2) is a receptor for cortistatin. It is probably involved in the function of nociceptive neurons and regulation of nociceptor function and/or development, including the sensation or modulation of pain. Cortistatin-14, a high potency agonist at the receptor, has biological functions including sleep regulation, locomotor activity and cortical function.

MAS1 belongs to the family of MAS-related orphan G protein coupled receptors, which are primarily expressed in primary sensory neurons and mast cells. The MAS-related GPCRs may be implicated in nociception, pruritus, sleep, cell proliferation, circulation, and mast cell degranulation. The MAS1 receptor when activated by binding angiotensin-(1-7) opposes many of the effects of angiotensin-II activated angiotensin receptor. Receptor agonists have similar therapeutic effects as angiotensin-II receptor antagonists including lowering blood pressure. Angiotensin peptide metabolites including angiotensin-III have also been reported to activate MAS1.

Orphan Cell Lines

Receptor FamilyReceptorSpeciesParentalStable Cell Lines Division-Arrested Cells Membranes
OrphanGPR3humanHEK293TC1091DC1091MC1091
GPR6humanHEK293TC1116DC1116MC1116
GPR6humanHEK293TC1116aDC1116aMC1116a
GPR15humanHEK293TC1069DC1069MC1069
GPR34humanHEK293T Gαqi5CG1095DCG1095MCG1095
GPR35dogHEK293T Gα16CGd1096DCGd1096MCGd1096
GPR35dogCHO-K1 Gα16CGd1096-1DCGd1096-1MCGd1096-1
GPR35mouseCHO-K1Cm1096-1DCm1096-1MCm1096-1
GPR35mouseCHO-K1 Gα16CGm1096-1DCGm1096-1MCGm1096-1
GPR35 (short form)humanCHO-K1C1096-1DC1096-1MC1096-1
GPR35 (short form)humanCHO-K1 β-Arrestin2CA1096-1DCA1096-1MCA1096-1
GPR35 (short form)humanCHO-K1 Gα16CG1096-1DCG1096-1MCG1096-1
GPR35 (short form)humanHEK293T Gα16CG1096DCG1096MCG1096
GPR35 (long form)humanCHO-K1 β-Arrestin2CA1523-1DCA1523-1MCA1523-1
GPR35 (long form) T108M MutanthumanCHO-K1 β-Arrestin2CA1524-1DCA1524-1MCA1524-1
GPR37L1humanHEK293TC1098DC1098MC1098
GPR45humanCHO-K1CG1106-1DCG1106-1MCG1106-1
GPR45humanCHO-K1CG1106-1aDCG1106-1aMCG1106-1a
GPR50humanHEK293TC1110DC1110MC1110
GPR52humanHEK293TC1112DC1112MC1112
GPR52humanHEK293TC1112aDC1112aMC1112a
GPR52humanHEK293T β-Arrestin2CA1112BA2DCA1112BA2MCA1112BA2
GPR85humanHEK293TC1138DC1138MC1138
GPR85humanCHO-K1C1138-1DC1138-1MC1138-1
GPR88humanCHO-K1C1141-1DC1141-1MC1141-1
GPR88ratCHO-K1Cr1141-1DCr1141-1MCr1141-1
GPR142humanHEK293TC1286DC1286MC1286
GPR142humanHEK293TC1286aDC1286aMC1286a
GPR151humanCHO-K1 Gα16 Gαqi5CG1181-1DCG1181-1MCG1181-1
GPRC5AhumanHEK293TCA1525DCA1525MCA1525
MRGX1humanCHO dhfr-Gαqi5C1256DC1256MC1256
MRGX2humanHEK293T Gαqi5C1257DC1257MC1257
MRGX2humanHEK293TC1257aDC1257aMC1257a
MRGX2rhesus monkeyCHO-K1Cpr1257-1DCpr1257-1MCpr1257-1
MRGX2humanHEK293T β-Arrestin2CA1257aBA2DCA1257aBA2MCA1257aBA2
MRGX2humanHEK293T β-Arrestin2CA1257bBA2DCA1257bBA2MCA1257bBA2
MRGX4humanHEK293TC1259DC1259MC1259
MAS1humanHEK293TC1225DC1225MC1225

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