Nomenclature: GPR6

Family: Class A Orphans

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


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
G-protein coupled receptor 6
Sphingosine 1-phosphate receptor
G protein-coupled receptor 6
putative G protein-coupled receptor (CNL3)
Database Links
Ensembl Gene
Entrez Gene
GenitoUrinary Development Molecular Anatomy Project
Human Protein Reference Database
PharmGKB Gene
Protein Ontology (PRO)
RefSeq Nucleotide
RefSeq Protein
UniGene Hs.
Natural/Endogenous Ligands
sphingosine 1-phosphate
Comments: Proposed ligand, single publication
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 5,13
pEC50 7.25 – 7.66 (EC50 5.6x10-8 – 2.2x10-8 M) [5,13]
Agonist Comments
An intial report that sphingosine-1-phosphate (S1P) was a high-affinity ligand (EC50 value of 39 nM) [5,13] has not been repeated by β-Arrestin PathHunter[TM] Assay [11,15].
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:  14
Putamen, frontal cortex, hippocampus, hypothalamus.
Species:  Human
Technique:  Northern blot
References:  3
Brain, testis and skeletal muscle
Species:  Mouse
Technique:  Northern blot
References:  5
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
Highly expressed in brain with a trace amount of mRNA detected in the testis.
Species:  Mouse
Technique:  RT-PCR
References:  12
Expression Datasets

Show »

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]

There should be a chart of expression data here, you may need to enable JavaScript!
Physiological Consequences of Altering Gene Expression
Promote cAMP mediated neurite growth
Species:  Rat
Tissue:  Primary cerebellar granule neurons
Technique:  Gene over-expression
References:  12
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

Show »

Allele Composition & genetic background Accession Phenotype Id Phenotype Reference
Gpr6tm1Dgen Gpr6tm1Dgen/Gpr6tm1Dgen
MGI:2155249  MP:0002062 abnormal conditioning behavior PMID: 17934457 
Gpr6tm1Dgen Gpr6tm1Dgen/Gpr6tm1Dgen
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 β-Arrestin Orphan GPCR Cell Line (Cat no. 93-0634C2)
PathHunter® eXpress GPR6 CHO-K1 β-Arrestin Orphan GPCR Assay (Cat no. 93-0634E2CP1M)
PathHunter® eXpress GPR6 U2OS β-Arrestin Orphan GPCR Assay (Cat no. 93-0634E3CP1M)
PathHunter® U2OS GPR6 β-Arrestin Orphan GPCR Cell Line (Cat no. 93-0634C3)
more info


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. Neurogenetics8 (3): 219-24. [PMID:17375343]

3. Heiber M, Docherty JM, Shah G, Nguyen T, Cheng R, Heng HH, Marchese A, Tsui LC, Shi X, George SR. (1995) Isolation of three novel human genes encoding G protein-coupled receptors. DNA Cell Biol14: 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. Neurogenetics7 (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. Genomics28 (2): 347-9. [PMID:8530049]

11. Southern C, Cook JM, Neetoo-Isseljee Z, Taylor DL, Kettleborough CA, Merritt A, Bassoni DL, Raab WJ, Quinn E, Wehrman TS et al.. (2013) Screening β-Arrestin Recruitment for the Identification of Natural Ligands for Orphan G-Protein-Coupled Receptors. J Biomol Screen18 (5): 599-609. [PMID:23396314]

12. 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]

13. 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]

14. 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]

15. 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]

To cite this database page, please use the following:

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: GPR6. Last modified on 01/08/2013. Accessed on 24/10/2014. IUPHAR database (IUPHAR-DB),

Contact us | Print | Back to top | Help
Copyright © 2014 IUPHAR