GPR3

Target id: 83

Nomenclature: GPR3

Family: Class A Orphans

Annotation status:  image of a green circle Annotated and expert reviewed. Please contact us if you can help with updates.  » Email us

   GtoImmuPdb view: OFF :     Currently no data for GPR3 in GtoImmuPdb

Gene and Protein Information
class A G protein-coupled receptor
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human 7 330 1p36.1-p35 GPR3 G protein-coupled receptor 3
Mouse 7 330 4 D3 Gpr3 G-protein coupled receptor 3
Rat 7 322 5q36 Gpr3 G protein-coupled receptor 3
Previous and Unofficial Names
Gpcr21
GPCR3
ACCA orphan receptor
adenylate cyclase constitutive activator
G protein-coupled receptor R4
Gpcr20
Database Links
Specialist databases
GPCRDB gpr3_human (Hs), gpr3_mouse (Mm), gpr3_rat (Rn)
Other databases
Ensembl Gene
Entrez Gene
GenitoUrinary Development Molecular Anatomy Project
KEGG Gene
OMIM
RefSeq Nucleotide
RefSeq Protein
UniProtKB
Wikipedia
Natural/Endogenous Ligands
sphingosine 1-phosphate
Comments: Proposed ligand, single publication

Download all structure-activity data for this target as a CSV file

Agonists
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Affinity Units Reference
sphingosine 1-phosphate Hs Full agonist 7.1 – 7.7 pEC50 7
pEC50 7.1 – 7.7 [7]
diphenyleneiodonium chloride Hs Full agonist 6.0 pEC50 9
pEC50 6.0 (EC50 1x10-6 M) [9]
Agonist Comments
Proposed ligand (sphingosine 1-phosphate), supported by one publication [7], this result was not repeated in β-arrestin assay [10] and so the GPR3 is still recognised as an orphan.
Primary Transduction Mechanisms
Transducer Effector/Response
Gs family Adenylate cyclase stimulation
Comments:  When expressed transiently in HEK293 cells, gpr3 confers constitutive activation of adenylate cyclase (AC) similar in amplitude to that seen with fully activated Gαs-coupled receptors
References:  1
Expression Datasets

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Log average relative transcript abundance in mouse tissues measured by qPCR from Regard, J.B., Sato, I.T., and Coughlin, S.R. (2008). Anatomical profiling of G protein-coupled receptor expression. Cell, 135(3): 561-71. [PMID:18984166] [Raw data: website]

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Physiological Functions
GPR3 is an antiproliferative mediator of cerebellar granule precursors (CGPs) in the postnatal development of murine cerebellum
Species:  Mouse
Tissue:  cerebellum
References:  5
Gs-linked receptor GPR3 maintains meiotic arrest in mammalian oocytes
Species:  Mouse
Tissue:  Oocytes
References:  3
Physiological Consequences of Altering Gene Expression
Premature termination of meiotic arrest in mammalian oocytes.
Species:  Mouse
Tissue: 
Technique:  Knockout mice
References:  3
Deletion of Gpr3 causes premature ovarian aging in mice
Species:  Mouse
Tissue: 
Technique:  Knockout mice
References:  2
GPR3 is highly expressed in areas of the normal human brain implicated in Alzheimer's disease and is elevated in the sporadic Alzheimer's disease brain.
Species:  Human
Tissue: 
Technique:  immunoblot analysis and densitometric quantification
References:  6
Gpr3(-/-) mice display low basal intracellular cAMP levels and behavioural analyses of the mice revealed a high level of avoidance of novel and unfamiliar environments and increased stress.
Species:  Mouse
Tissue: 
Technique:  Knockout mice
References:  8
Genetic ablation of GPR3 prevented accumulation of the amyloid-β peptide in vitro and in an Alzheimer's disease mouse model
Species:  Mouse
Tissue:  Brain
Technique:  Gene knockouts
References:  6
Hypersensitivity to thermal non-noxious and noxious stimuli
Species:  Human
Tissue:  Spinal chord
Technique:  Gene knockouts
References:  4
Phenotypes, Alleles and Disease Models Mouse data from MGI

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Allele Composition & genetic background Accession Phenotype Id Phenotype Reference
Gpr3tm1Cled Gpr3tm1Cled/Gpr3tm1Cled
either: B6.129-Gpr3 or (involves: 129S1/Sv * 129X1/SvJ * CD-1)
MGI:101908  MP:0005168 abnormal female meiosis PMID: 15956199 
Gpr3tm1Cled Gpr3tm1Cled/Gpr3tm1Cled
either: B6.129-Gpr3 or (involves: 129S1/Sv * 129X1/SvJ * CD-1)
MGI:101908  MP:0003699 abnormal female reproductive system physiology PMID: 15956199 
Gpr3tm1Cled Gpr3tm1Cled/Gpr3tm1Cled
either: B6.129-Gpr3 or (involves: 129S1/Sv * 129X1/SvJ * CD-1)
MGI:101908  MP:0001125 abnormal oocyte morphology PMID: 15956199 
Gpr3tm1Cled Gpr3tm1Cled/Gpr3tm1Cled
either: B6.129-Gpr3 or (involves: 129S1/Sv * 129X1/SvJ * CD-1)
MGI:101908  MP:0001931 abnormal oogenesis PMID: 15956199 
Gpr3tm1Cled Gpr3tm1Cled/Gpr3tm1Cled
either: B6.129-Gpr3 or (involves: 129S1/Sv * 129X1/SvJ * CD-1)
MGI:101908  MP:0001935 decreased litter size PMID: 15956199 
Gpr3tm1Cled Gpr3tm1Cled/Gpr3tm1Cled
either: B6.129-Gpr3 or (involves: 129S1/Sv * 129X1/SvJ * CD-1)
MGI:101908  MP:0001750 increased circulating follicle stimulating hormone level PMID: 15956199 
Gpr3tm1Dgen Gpr3tm1Dgen/Gpr3tm1Dgen
involves: 129P2/OlaHsd * C57BL/6
MGI:101908  MP:0001973 increased thermal nociceptive threshold
Gpr3tm1Cled Gpr3tm1Cled/Gpr3tm1Cled
either: B6.129-Gpr3 or (involves: 129S1/Sv * 129X1/SvJ * CD-1)
MGI:101908  MP:0003718 maternal effect PMID: 15956199 
Gpr3tm1Cled Gpr3tm1Cled/Gpr3tm1Cled
either: B6.129-Gpr3 or (involves: 129S1/Sv * 129X1/SvJ * CD-1)
MGI:101908  MP:0001923 reduced female fertility PMID: 15956199 
Gpr3tm1Cled Gpr3tm1Cled/Gpr3tm1Cled
either: B6.129-Gpr3 or (involves: 129S1/Sv * 129X1/SvJ * CD-1)
MGI:101908  MP:0009007 short estrous cycle PMID: 15956199 
Clinically-Relevant Mutations and Pathophysiology
Disease:  Alzheimer disease
Synonyms: Alzheimer's disease [Disease Ontology: DOID:10652]
Disease Ontology: DOID:10652
OMIM: 104300
Role: 
References:  6
Biologically Significant Variants
Type:  Single nucleotide polymorphism
Species:  Human
Amino acid change:  R222H
Global MAF (%):  1
Subpopulation MAF (%):  AFR: 6
Minor allele count:  A=0.014/31
Comment on frequency:  Low frequency (<10% in all tested populations)
SNP accession: 
Validation:  1000 Genomes, HapMap
General Comments
A study suggests that GPR3 normal function is involved in the modulation of behavioral responses to stress [8].

References

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1. Eggerickx D, Denef JF, Labbe O, Hayashi Y, Refetoff S, Vassart G, Parmentier M, Libert F. (1995) Molecular cloning of an orphan G-protein-coupled receptor that constitutively activates adenylate cyclase. Biochem. J.309 ( Pt 3): 837-43. [PMID:7639700]

2. Ledent C, Demeestere I, Blum D, Petermans J, Hämäläinen T, Smits G, Vassart G. (2005) Premature ovarian aging in mice deficient for Gpr3. Proc Natl Acad Sci U S A102: 8922-8926. [PMID:15956199]

3. Mehlmann LM, Saeki Y, Tanaka S, Brennan TJ, Evsikov AV, Pendola FL, Knowles BB, Eppig JJ, Jaffe LA. (2004) The Gs-linked receptor GPR3 maintains meiotic arrest in mammalian oocytes. Science306: 1947-1950. [PMID:15591206]

4. Ruiz-Medina J, Ledent C, Valverde O. (2011) GPR3 orphan receptor is involved in neuropathic pain after peripheral nerve injury and regulates morphine-induced antinociception. Neuropharmacology61 (1-2): 43-50. [PMID:21352831]

5. Tanaka S, Shaikh IM, Chiocca EA, Saeki Y. (2009) The Gs-linked receptor GPR3 inhibits the proliferation of cerebellar granule cells during postnatal development. PLoS One.4: 5922-5922. [PMID:19526062]

6. Thathiah A, Spittaels K, Hoffmann M, Staes M, Cohen A, Horré K, Vanbrabant M, Coun F, Baekelandt V, Delacourte A, Fischer DF, Pollet D, De Strooper B, Merchiers P. (2009) The orphan G protein-coupled receptor 3 modulates amyloid-beta peptide generation in neurons. Science323: 946-951. [PMID:19213921]

7. Uhlenbrock K, Gassenhuber H, Kostenis E. (2002) Sphingosine 1-phosphate is a ligand of the human gpr3, gpr6 and gpr12 family of constitutively active G protein-coupled receptors. Cell Signal14: 941-953. [PMID:12220620]

8. Valverde O, Célérier E, Baranyi M, Vanderhaeghen P, Maldonado R, Sperlágh B, Vassart G, Ledent C. (2009) GPR3 receptor, a novel actor in the emotional-like responses. PLoS One.4: 4704-4704. [PMID:19259266]

9. Ye C, Zhang Z, Wang Z, Hua Q, Zhang R, Xie X. (2014) Identification of a novel small-molecule agonist for human G protein-coupled receptor 3. J. Pharmacol. Exp. Ther.349 (3): 437-43. [PMID:24633425]

10. Yin H, Chu A, Li W, Wang B, Shelton F, Otero F, Nguyen DG, Caldwell JS, Chen YA. (2009) Lipid G protein-coupled receptor ligand identification using beta-arrestin PathHunter assay. J Biol Chem284: 12328-12338. [PMID:19286662]

Contributors

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How to cite this page

Anthony P. Davenport, Stephen Alexander, Joanna L. Sharman, Adam J. Pawson, Helen E. Benson, Amy E. Monaghan, Wen Chiy Liew, Chido Mpamhanga, Jim Battey, Richard V. Benya, Robert T. Jensen, Sadashiva Karnik, Evi Kostenis, Eliot Spindel, Laura Storjohann, Kalyan Tirupula, Tom I. Bonner, Richard Neubig, Jean-Philippe Pin, Michael Spedding, Anthony Harmar.
Class A Orphans: GPR3. Last modified on 30/07/2015. Accessed on 16/08/2017. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=83.