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 Family	Receptor	Species	Parental	Stable Cell Lines	Division-Arrested Cells	Membranes
Orphan	GPR3	human	HEK293T	C1091	DC1091	MC1091
	GPR6	human	HEK293T	C1116	DC1116	MC1116
	GPR6	human	HEK293T	C1116a	DC1116a	MC1116a
	GPR15	human	HEK293T	C1069	DC1069	MC1069
	GPR34	human	HEK293T Gαqi5	CG1095	DCG1095	MCG1095
	GPR35	dog	HEK293T Gα16	CGd1096	DCGd1096	MCGd1096
	GPR35	dog	CHO-K1 Gα16	CGd1096-1	DCGd1096-1	MCGd1096-1
	GPR35	mouse	CHO-K1	Cm1096-1	DCm1096-1	MCm1096-1
	GPR35	mouse	CHO-K1 Gα16	CGm1096-1	DCGm1096-1	MCGm1096-1
	GPR35 (short form)	human	CHO-K1	C1096-1	DC1096-1	MC1096-1
	GPR35 (short form)	human	CHO-K1 β-Arrestin2	CA1096-1	DCA1096-1	MCA1096-1
	GPR35 (short form)	human	CHO-K1 Gα16	CG1096-1	DCG1096-1	MCG1096-1
	GPR35 (short form)	human	HEK293T Gα16	CG1096	DCG1096	MCG1096
	GPR35 (long form)	human	CHO-K1 β-Arrestin2	CA1523-1	DCA1523-1	MCA1523-1
	GPR35 (long form) T108M Mutant	human	CHO-K1 β-Arrestin2	CA1524-1	DCA1524-1	MCA1524-1
	GPR37L1	human	HEK293T	C1098	DC1098	MC1098
	GPR45	human	CHO-K1	CG1106-1	DCG1106-1	MCG1106-1
	GPR45	human	CHO-K1	CG1106-1a	DCG1106-1a	MCG1106-1a
	GPR50	human	HEK293T	C1110	DC1110	MC1110
	GPR52	human	HEK293T	C1112	DC1112	MC1112
	GPR52	human	HEK293T	C1112a	DC1112a	MC1112a
	GPR52	human	HEK293T β-Arrestin2	CA1112BA2	DCA1112BA2	MCA1112BA2
	GPR85	human	HEK293T	C1138	DC1138	MC1138
	GPR85	human	CHO-K1	C1138-1	DC1138-1	MC1138-1
	GPR88	human	CHO-K1	C1141-1	DC1141-1	MC1141-1
	GPR88	rat	CHO-K1	Cr1141-1	DCr1141-1	MCr1141-1
	GPR142	human	HEK293T	C1286	DC1286	MC1286
	GPR142	human	HEK293T	C1286a	DC1286a	MC1286a
	GPR151	human	CHO-K1 Gα16 Gαqi5	CG1181-1	DCG1181-1	MCG1181-1
	GPRC5A	human	HEK293T	CA1525	DCA1525	MCA1525
	MRGX1	human	CHO dhfr-Gαqi5	C1256	DC1256	MC1256
	MRGX2	human	HEK293T Gαqi5	C1257	DC1257	MC1257
	MRGX2	human	HEK293T	C1257a	DC1257a	MC1257a
	MRGX2	rhesus monkey	CHO-K1	Cpr1257-1	DCpr1257-1	MCpr1257-1
	MRGX2	human	HEK293T β-Arrestin2	CA1257aBA2	DCA1257aBA2	MCA1257aBA2
	MRGX2	human	HEK293T β-Arrestin2	CA1257bBA2	DCA1257bBA2	MCA1257bBA2
	MRGX4	human	HEK293T	C1259	DC1259	MC1259
	MAS1	human	HEK293T	C1225	DC1225	MC1225