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GPR6

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Target id: 85

Nomenclature: GPR6

Family: Class A Orphans

Contents:

Gene and Protein Information Click here for help
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 12
Mouse 7 363 10 22.08 cM Gpr6 G protein-coupled receptor 6
Rat 7 363 20q12 Gpr6 G protein-coupled receptor 6
Previous and Unofficial Names Click here for help
Sphingosine 1-phosphate receptor GPR6
Database Links Click here for help
Specialist databases
GPCRdb gpr6_human (Hs), gpr6_mouse (Mm), gpr6_rat (Rn)
Other databases
Alphafold P46095 (Hs), Q6YNI2 (Mm), P51651 (Rn)
ChEMBL Target CHEMBL3714130 (Hs)
Ensembl Gene ENSG00000146360 (Hs), ENSMUSG00000046922 (Mm), ENSRNOG00000049580 (Rn)
Entrez Gene 2830 (Hs), 140741 (Mm), 83683 (Rn)
Human Protein Atlas ENSG00000146360 (Hs)
KEGG Gene hsa:2830 (Hs), mmu:140741 (Mm), rno:83683 (Rn)
OMIM 600553 (Hs)
Pharos P46095 (Hs)
RefSeq Nucleotide NM_005284 (Hs), NM_199058 (Mm), NM_031806 (Rn)
RefSeq Protein NP_005275 (Hs), NP_951013 (Mm), NP_113994 (Rn)
UniProtKB P46095 (Hs), Q6YNI2 (Mm), P51651 (Rn)
Wikipedia GPR6 (Hs)
Natural/Endogenous Ligands Click here for help
sphingosine 1-phosphate
Comments: Proposed ligand, single publication

Download all structure-activity data for this target as a CSV file go icon to follow link

Agonists
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
solangepras Small molecule or natural product Ligand has a PDB structure Hs Inverse agonist 8.0 pKi 14
⤷ pKi 8.0 (Ki 9.4x10-9 M) [14]
sphingosine 1-phosphate Small molecule or natural product Click here for species-specific activity table Ligand is endogenous in the given species Ligand has a PDB structure Mm Full agonist 7.3 – 7.7 pEC50 7,16
⤷ pEC50 7.3 – 7.7 (EC50 5.6x10-8 – 2.2x10-8 M) [7,16]
example 31 [WO2018183145] Small molecule or natural product Hs Inverse agonist 7.1 pEC50 3
⤷ pEC50 7.1 (EC50 7.94x10-8 M) [3]
Description: Inhibition of GPR6 constitutive cAMP activity in CHO-K1 cells.
example 494 [WO2014028479] parent molecule Small molecule or natural product Hs Inverse agonist 8.7 pIC50 5
⤷ pIC50 8.7 (IC50 2x10-9 M) [5]
Description: Inhibition of GPR6 constitutive cAMP activity
View species-specific agonist tables
Agonist Comments
An intial report that sphingosine-1-phosphate (S1P) was a high-affinity ligand (EC50 value of 39 nM) [7,16] has not been repeated by β-Arrestin PathHunter[TM] Assay [13,18].
Primary Transduction Mechanisms Click here for help
Transducer Effector/Response
Gs family
Gi/Go family 		Adenylyl cyclase stimulation
Adenylyl cyclase inhibition
References:  6,10
Tissue Distribution Click here for help
Putamen, frontal cortex, hippocampus, hypothalamus.
Species:  Human
Technique:  Northern blot
References:  4
Nucleus accumbens, putamen
Species:  Human
Technique:  Microarray analysis and RT-PCR
References:  2,11
Endothelial cells of pulmonary artery, lung, coronary artery and umbilical vein
Species:  Human
Technique:  RT-PCR
References:  17
Brain, testis and skeletal muscle
Species:  Mouse
Technique:  Northern blot
References:  7
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:  9
Highly expressed in brain with a trace amount of mRNA detected in the testis.
Species:  Mouse
Technique:  RT-PCR
References:  15
Expression Datasets Click here for help

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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 Consequences of Altering Gene Expression Click here for help
Promote cAMP mediated neurite growth
Species:  Rat
Tissue:  Primary cerebellar granule neurons
Technique:  Gene over-expression
References:  15
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:  9
Phenotypes, Alleles and Disease Models Click here for help 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 [8]. The expression of GPR6 is upregulated in central extended amygdala after excessive μ receptor activation [1].

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. Green J, Hopkins M, Jones B, Kiryanov AA, Kuehler J, Monenschein H, Murphy S, Nixey T, Sun H. (2018) Piperidinyl- and piperazinyl-substituted heteroaromatic carboxamides as modulators of gpr6. Patent number: WO2018183145A1. Assignee: Takeda Pharmaceutical Company Limited. Priority date: 26/03/2018. Publication date: 04/10/2018.

4. Heiber M, Docherty JM, Shah G, Nguyen T, Cheng R, Heng HH, Marchese A, Tsui LC, Shi X, George SR et al.. (1995) Isolation of three novel human genes encoding G protein-coupled receptors. DNA Cell Biol, 14 (1): 25-35. [PMID:7832990]

5. Hitchcock S, Monenschein H, Reichard H, Sun H, Macklin T, Hopkins M. (2014) Quinoxaline derivatives as gpr6 modulators. Patent number: WO2014028479A1. Assignee: Envoy Therapeutics, Inc.. Priority date: 13/08/2013. Publication date: 20/02/2014.

6. 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]

7. 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]

8. 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]

9. 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]

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

11. 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]

12. 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]

13. 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 Screen, 18 (5): 599-609. [PMID:23396314]

14. Sun H, Monenschein H, Schiffer HH, Reichard HA, Kikuchi S, Hopkins M, Macklin TK, Hitchcock S, Adams M, Green J et al.. (2021) First-Time Disclosure of CVN424, a Potent and Selective GPR6 Inverse Agonist for the Treatment of Parkinson's Disease: Discovery, Pharmacological Validation, and Identification of a Clinical Candidate. J Med Chem, 64 (14): 9875-9890. [PMID:33861086]

15. 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]

16. 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 Signal, 14: 941-953. [PMID:12220620]

17. 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]

18. 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 Chem, 284: 12328-12338. [PMID:19286662]

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