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GPR6

Family: Class A Orphans

Contents:
Gene and Protein Information
Previous and Unofficial Names
Database Links
Agonists
Transduction Mechanisms
Tissue Distribution
Expression Datasets
Physiological Consequences of Altering Gene Expression
Phenotypes, Alleles and Disease Models
General Comments
References
Gene and Protein Information
class A G protein-coupled receptor
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human 7 362 6q21 GPR6 G protein-coupled receptor 6 10
Mouse 7 363 10 B2 Gpr6 G protein-coupled receptor 6
Rat 7 363 20 Gpr6 G protein-coupled receptor 6
Previous and Unofficial Names
Sphingosine 1-phosphate receptor GPR6
GPR6
G-protein coupled receptor 6
Sphingosine 1-phosphate receptor
G protein-coupled receptor 6
putative G protein-coupled receptor (CNL3)
AI852874
Gm233
Database Links
Ensembl ENSG00000146360 (Hs), ENSMUSG00000046922 (Mm)
Entrez Gene 2830 (Hs), 140741 (Mm), 83683 (Rn)
GeneCards GPR6 (Hs)
GenitoUrinary Development Molecular Anatomy Project Gpr6 (Mm)
HomoloGene 38026 (Hs)
Human Protein Reference Database 02775 (Hs)
InterPro P46095 (Hs), Q6YNI2 (Mm), P51651 (Rn)
KEGG Gene hsa:2830 (Hs), mmu:140741 (Mm), rno:83683 (Rn)
OMIM 600553 (Hs)
PharmGKB Gene PA28904 (Hs)
Protein Ontology (PRO) PRO:000001674 (Hs)
RefSeq Nucleotide NM_005284 (Hs), NM_199058 (Mm), NM_031806 (Rn)
RefSeq Protein NP_005275 (Hs), NP_951013 (Mm), NP_113994 (Rn)
TreeFam ENSG00000146360 (Hs), ENSMUSG00000046922 (Mm)
UniGene Hs. 46332 (Hs)
UniProt P46095 (Hs), Q6YNI2 (Mm), P51651 (Rn)
Wikipedia GPR6
Orphan and other 7TM receptors
Natural/Endogenous Ligand(s)
sphingosine 1-phosphate
Comments: Proposed ligand, single publication
Agonists
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Affinity Units Reference
sphingosine 1-phosphate Mm Full agonist 7.25 – 7.66 pEC50 5,12
Agonist Comments
An intial report of that sphingosine-1-phosphate (S1P) was a high-affinity ligand (EC50 value of 39 nM) [5] has not been repeated by β-Arrestin PathHunter[TM] Assay [14].
Primary Transduction Mechanisms
Transducer Effector/Response
Gs family
Gi/Go family 		Adenylate cyclase stimulation
Adenylate cyclase inhibition
References:  4,8
Tissue Distribution
Nucleus accumbens, putamen
Species:  Human
Technique:  Microarray analysis and RT-PCR
References:  2,9
Endothelial cells of pulmonary artery, lung, coronary artery and umbilical vein
Species:  Human
Technique:  RT-PCR
References:  13
Putamen, frontal cortex, hippocampus, hypothalamus.
Species:  Human
Technique:  Northern blot
References:  3
Brain, testis and skeletal muscle
Species:  Mouse
Technique:  Northern blot
References:  5
Highly expressed in brain with a trace amount of mRNA was detected in the testis.
Species:  Mouse
Technique:  RT-PCR
References:  11
Striatopallidal medium spiny neurons
Species:  Mouse
Technique:  RT-PCR and and GFP staining in transgenic mice expressing GFP under the control of Gpr6 regulatory element
References:  7
Tissue Distribution Comments
It is shown that GPR6 is located in the intracellular compartments [8].
Expression Datasets

Click here to show/hide data

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 Consequences of Altering Gene Expression
Promote cAMP mediated neurite growth
Species:  Rat
Tissue:  Primary cerebellar granule neurons
Technique:  Gene over-expression
References:  11
Gpr6-deficient mice showed reduced striatal cyclic AMP production in vitro and selected alterations in instrumental conditioning in vitro.
Species:  Mouse
Tissue:  Striatopallidal medium spiny neurons
Technique:  Gene knockout
References:  7
Phenotypes, Alleles and Disease Models Mouse data from MGI

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Allele Composition & genetic background Accession Phenotype Id Phenotype Reference
Gpr6tm1Dgen Gpr6tm1Dgen/Gpr6tm1Dgen
B6.129P2-Gpr6		 MGI:2155249  MP:0002062 abnormal conditioning behavior PMID: 17934457 
Gpr6tm1Dgen Gpr6tm1Dgen/Gpr6tm1Dgen
B6.129P2-Gpr6		 MGI:2155249  MP:0004077 abnormal striatum morphology PMID: 17934457 
Gpr6tm1Dgen Gpr6tm1Dgen/Gpr6tm1Dgen
involves: 129P2/OlaHsd * C57BL/6		 MGI:2155249  MP:0002169 no abnormal phenotype detected
General Comments
GPR6 was found to be able to stimulate strong ligand-independent adenylyl cyclase activation [6]. The expression of GPR6 is upregulated in central extended amygdala after excessive mu receptor activation [1].
Available Assays
DiscoveRx PathHunter® CHO-K1 GPR6 (Orphan) High Expression β-Arrestin Cell Line Human Cat No. 93-0634C2
DiscoveRx PathHunter® eXpress GPR6 CHO-K1 β-Arrestin (Orphan) GPCR Assay Human Cat No. 93-0634E2CP1
DiscoveRx PathHunter® eXpress GPR6 U2OS β-Arrestin (Orphan) GPCR Assay Human Cat No. 93-0634E3CP1
DiscoveRx PathHunter® U2OS GPR6 (Orphan) High Expression β-Arrestin Cell Line Human Cat No. 93-0634C3

REFERENCES

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1. Befort, K; Filliol, D; Ghate, A; Darcq, E; Matifas, A; Muller, J; Lardenois, A; Thibault, C; Dembele, D; Le Merrer, J; Becker, JA; Poch, O; Kieffer, BL. (2008) Mu-opioid receptor activation induces transcriptional plasticity in the central extended amygdala. Eur. J. Neurosci., 27 (11): 2973-84. [PMID:18588537]

2. Ernst, C; Sequeira, A; Klempan, T; Ernst, N; Ffrench-Mullen, J; Turecki, G. (2007) Confirmation of region-specific patterns of gene expression in the human brain. Neurogenetics, 8 (3): 219-24. [PMID:17375343]

3. Heiber, M., Docherty, J. M., Shah, G., Nguyen, T., Cheng, R., Heng, H. H., Marchese, A., Tsui, L. C., Shi, X. and George, S. R. (1995) Isolation of three novel human genes encoding G protein-coupled receptors. DNA Cell Biol, 14: 25-35. [PMID:7832990]

4. Ignatov, A; Lintzel, J; Hermans-Borgmeyer, I; Kreienkamp, HJ; Joost, P; Thomsen, S; Methner, A; Schaller, HC. (2003) Role of the G-protein-coupled receptor GPR12 as high-affinity receptor for sphingosylphosphorylcholine and its expression and function in brain development. J. Neurosci., 23 (3): 907-14. [PMID:12574419]

5. Ignatov, A; Lintzel, J; Kreienkamp, HJ; Schaller, HC. (2003) Sphingosine-1-phosphate is a high-affinity ligand for the G protein-coupled receptor GPR6 from mouse and induces intracellular Ca2+ release by activating the sphingosine-kinase pathway. Biochem. Biophys. Res. Commun., 311 (2): 329-36. [PMID:14592418]

6. Kostenis, E. (2004) Novel clusters of receptors for sphingosine-1-phosphate, sphingosylphosphorylcholine, and (lyso)-phosphatidic acid: new receptors for "old" ligands. J. Cell. Biochem., 92 (5): 923-36. [PMID:15258916]

7. Lobo, MK; Cui, Y; Ostlund, SB; Balleine, BW; Yang, XW. (2007) Genetic control of instrumental conditioning by striatopallidal neuron-specific S1P receptor Gpr6. Nat. Neurosci., 10 (11): 1395-7. [PMID:17934457]

8. Padmanabhan, S; Myers, AG; Prasad, BM. (2009) Constitutively active GPR6 is located in the intracellular compartments. FEBS Lett., 583 (1): 107-12. [PMID:19059244]

9. Roth, RB; Hevezi, P; Lee, J; Willhite, D; Lechner, SM; Foster, AC; Zlotnik, A. (2006) Gene expression analyses reveal molecular relationships among 20 regions of the human CNS. Neurogenetics, 7 (2): 67-80. [PMID:16572319]

10. Song, ZH; Modi, W; Bonner, TI. (1995) Molecular cloning and chromosomal localization of human genes encoding three closely related G protein-coupled receptors. Genomics, 28 (2): 347-9. [PMID:8530049]

11. Tanaka, S; Ishii, K; Kasai, K; Yoon, SO; Saeki, Y. (2007) Neural expression of G protein-coupled receptors GPR3, GPR6, and GPR12 up-regulates cyclic AMP levels and promotes neurite outgrowth. J. Biol. Chem., 282 (14): 10506-15. [PMID:17284443]

12. Uhlenbrock, K., Gassenhuber, H. and 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 Signal, 14: 941-953. [PMID:12220620]

13. Uhlenbrock, K; Huber, J; Ardati, A; Busch, AE; Kostenis, E. (2003) Fluid shear stress differentially regulates gpr3, gpr6, and gpr12 expression in human umbilical vein endothelial cells. Cell. Physiol. Biochem., 13 (2): 75-84. [PMID:12649592]

14. Yin, H., Chu, A., Li, W., Wang, B., Shelton, F., Otero, F., Nguyen, D.G., Caldwell, J.S. and Chen, Y.A. (2009) Lipid G protein-coupled receptor ligand identification using beta-arrestin PathHunter assay. J Biol Chem, 284: 12328-12338. [PMID:19286662]

To cite this database page, please use the following:

Wen Chiy Liew.
Class A Orphans: GPR6. Last modified on 26/07/2012. Accessed on 20/05/2013. IUPHAR database (IUPHAR-DB), http://www.iuphar-db.org/DATABASE/ObjectDisplayForward?objectId=85.


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