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Gene and Protein Information  |
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| 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 |
| Sphingosine 1-phosphate receptor GPR6 |
| Database Links |
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| 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 |
| sphingosine 1-phosphate |
| Comments: Proposed ligand, single publication |
Download all structure-activity data for this target as a CSV file 
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| Key to terms and symbols | View all chemical structures | Click column headers to sort | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| 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
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| Transducer | Effector/Response |
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Gs family Gi/Go family |
Adenylyl cyclase stimulation Adenylyl cyclase inhibition |
| References: 6,10 | |
| Tissue Distribution
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| Expression Datasets |
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| Physiological Consequences of Altering Gene Expression
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| Phenotypes, Alleles and Disease Models
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Mouse data from MGI | ||||||||||||||||||||||||
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| 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]. |
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]
