GPR65

Psychosine receptor is a G protein-coupled receptor (GPCR) protein that in humans is encoded by the GPR65 gene.[5][6] GPR65 is also referred to as TDAG8.

GPR65
Identifiers
Aliases	GPR65, TDAG8, hTDAG8, G protein-coupled receptor 65
External IDs	OMIM: 604620 MGI: 108031 HomoloGene: 2675 GeneCards: GPR65
Gene location (Human) Chr. Chromosome 14 (human)[1] Band 14q31.3 Start 88,005,135 bp[1] End 88,014,811 bp[1]
Gene location (Mouse) Chr. Chromosome 12 (mouse)[2] Band 12|12 E Start 98,268,635 bp[2] End 98,276,644 bp[2]
RNA expression pattern More reference expression data
Gene ontology Molecular function • G-protein coupled receptor activity • signal transducer activity Cellular component • integral component of membrane • cell membrane • integral component of plasma membrane • membrane • intracellular Biological process • multicellular organism development • actin cytoskeleton reorganization • immune response • positive regulation of stress fiber assembly • GO:0032861, GO:0032862, GO:0032856 activation of GTPase activity • response to acidic pH • signal transduction • apoptotic process • positive regulation of Rho protein signal transduction • positive regulation of cytosolic calcium ion concentration involved in phospholipase C-activating G-protein coupled signaling pathway • G-protein coupled receptor signaling pathway • adenylate cyclase-activating G-protein coupled receptor signaling pathway Sources:Amigo / QuickGO
Orthologs
Species	Human	Mouse
Entrez	8477	14744
Ensembl	ENSG00000140030	ENSMUSG00000021886
UniProt	Q8IYL9	Q61038
RefSeq (mRNA)	NM_003608	NM_008152
RefSeq (protein)	NP_003599	NP_032178
Location (UCSC)	Chr 14: 88.01 – 88.01 Mb	Chr 12: 98.27 – 98.28 Mb
PubMed search	[3]	[4]
Wikidata
View/Edit Human View/Edit Mouse

Species, tissue, and subcellular distribution

GPR65 (TDAG8) is primarily expressed in lymphoid tissues (spleen, lymph nodes, thymus, and leukocytes),[7] and as a GPCR, the protein is localized to the plasma membrane.

Function

Ligand binding

In 2001, GPR65 was reported to be a specific receptor for psychosine (d-galactosyl-β-1,1′ sphingosine) as well as several other related glycosphingolipids.[8] However, the specific binding of psychosine to GPR65 has been contested as the reported ligand binding did not satisfy the appropriate pharmacological criteria.[9]

More recently, 3-[(2,4-dichlorophenyl)methylsulfanyl]-1,6-dimethylpyridazino[4,5-e][1,3,4]thiadiazin-5-one (referred to as BTB09089) was found to be a specific agonist for GPR65.[10] Furthermore, [(S)-phenyl(pyridin-4-yl)methyl] 4-methyl-2-pyrimidin-2-yl-1,3-thiazole-5-carboxylate (referred to as ZINC62678696) was found to act as a BTB09089 negative allosteric modulator.[11]

pH sensing

GPR65 senses extracellular pH.[12] Levels of cyclic adenosine monophosphate (cAMP), a secondary messenger associated with activation of GPCRs in the cAMP-dependent pathway, were found to be elevated in neutral to acidic extracellular pH (pH 7.0-6.5) in cells expressing GPR65. In cells with mutated GPR65, this pH-sensing effect was reduced or eliminated. In the presence of psychosine, however, the levels of cAMP increased at a shifted, more acidic pH range. As such, psychosine displayed an inhibitory effect as an antagonist when GPR65 was stimulated with an increasing concentration of protons (increasingly acidic pH). This finding directly contested the previous reporting of psychosine as an activating ligand for GPR65.

The pH-sensing ability of GPR65 was further tested and confirmed, as it was found that cAMP levels increased when GPR65 was stimulated by pH values less than pH 7.2.[13]

GPR65 senses pH by protonation of histidine residues on its extracellular domain, and when activated, GPR65 enables the downstream signaling through the Gq/11, Gs, and G12/13 pathways.[14] The ability of GPR65 to sense pH can modulate several cellular functions in various biological systems including the immune, cardiovascular, respiratory, renal, and nervous systems.[15]

GPR65's ability to sense pH plays a prominent role in tumor development.[16] GPR65 is highly expressed in a variety of human tumors. Tumor development is associated with low extracellular pH due to changes in metabolism of rapidly dividing cells. GPR65 enables tumor growth by sensing the acidic environment. It was found that overexpression of GPR65 prevents tumor cell death in acidic conditions in vitro and facilitates tumor growth in vivo.

Immune

GPR65 reduces immune-mediated inflammation by regulating cytokine production of T cells (including IL-6, TNF-α and IL-1β) and macrophages.[17]

Cardiovascular

After myocardial infarction, anaerobic respiration and severe inflammation occurs—both of which are accompanied by an acidic environment. GPR65 knockout mice showed a decline in survival and cardiac function after myocardial infarction, which indicates that GPR65-mediated pH sensing is physiologically relevant. GPR65 exhibits a cardioprotective effect against myocardial infarction by reducing CCL20 expression and the migration of IL-17A-producing γδT cells that express CCR6, a receptor for CCL20.[18]

Visual

Retinal function is sensitive to changes in pH. It was found that GPR65 is overexpressed in the retina of mouse models of retinal degeneration and that the receptor supports the survival of photoreceptors in a degenerating retina by sensing pH and activating microglia after light-injury.[19]

Gastrointestinal

Vagal afferents expressing GPR65 innervate intestinal villi. These GPR65-expressing vagal afferents detect nutrients in the intestinal lumen and also slow gut motility.[20]

Depression

GPR65 was identified as a potential target linking inflammation and depression. GPR65 knockout mice exhibited a significant reduction in mobility in a forced swim test as well as higher consumption of sucrose—both of which are behaviors associated with depression.[21]

History/Discovery

In 1996, Choi et al. first identified GPR65 (TDAG8) as a G protein-coupled receptor whose expression was induced during activation-induced apoptosis of T cells.[22] The group sought to identify which genes were necessary during T cell receptor-mediated death of immature thymocytes, and using differential mRNA display, they found that TDAG8 expression was induced upon activation of T cells. Because this gene was found to be associated with T-cell death (apoptosis), it was named TDAG8, or T Cell Death Associated Gene 8.

See also

• Proton-sensing G protein-coupled receptors

References

1. GRCh38: Ensembl release 89: ENSG00000140030 - Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000021886 - Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. Kyaw H, Zeng Z, Su K, Fan P, Shell BK, Carter KC, Li Y (June 1998). "Cloning, characterization, and mapping of human homolog of mouse T-cell death-associated gene". DNA and Cell Biology. 17 (6): 493–500. doi:10.1089/dna.1998.17.493. PMID 9655242.
6. "Entrez Gene: GPR65 G protein-coupled receptor 65".
7. Choi JW, Lee SY, Choi Y (February 1996). "Identification of a putative G protein-coupled receptor induced during activation-induced apoptosis of T cells". Cellular Immunology. 168 (1): 78–84. doi:10.1006/cimm.1996.0051. PMID 8599842.
8. Im DS, Heise CE, Nguyen T, O'Dowd BF, Lynch KR (April 2001). "Identification of a molecular target of psychosine and its role in globoid cell formation". The Journal of Cell Biology. 153 (2): 429–34. doi:10.1083/jcb.153.2.429. PMC 2169470. PMID 11309421.
9. Im DS (March 2004). "Discovery of new G protein-coupled receptors for lipid mediators". Journal of Lipid Research. 45 (3): 410–8. doi:10.1194/jlr.R300006-JLR200. PMID 14657204.
10. Onozawa Y, Fujita Y, Kuwabara H, Nagasaki M, Komai T, Oda T (May 2012). "Activation of T cell death-associated gene 8 regulates the cytokine production of T cells and macrophages in vitro". European Journal of Pharmacology. 683 (1–3): 325–31. doi:10.1016/j.ejphar.2012.03.007. PMID 22445881.
11. Huang XP, Karpiak J, Kroeze WK, Zhu H, Chen X, Moy SS, Saddoris KA, Nikolova VD, Farrell MS, Wang S, Mangano TJ, Deshpande DA, Jiang A, Penn RB, Jin J, Koller BH, Kenakin T, Shoichet BK, Roth BL (2015). "Allosteric ligands for the pharmacologically dark receptors GPR68 and GPR65". Nature. 527 (7579): 477–83. doi:10.1038/nature15699. PMC 4796946. PMID 26550826.
12. Wang JQ, Kon J, Mogi C, Tobo M, Damirin A, Sato K, Komachi M, Malchinkhuu E, Murata N, Kimura T, Kuwabara A, Wakamatsu K, Koizumi H, Uede T, Tsujimoto G, Kurose H, Sato T, Harada A, Misawa N, Tomura H, Okajima F (October 2004). "TDAG8 is a proton-sensing and psychosine-sensitive G-protein-coupled receptor". The Journal of Biological Chemistry. 279 (44): 45626–33. doi:10.1074/jbc.M406966200. PMID 15326175.
13. Ishii S, Kihara Y, Shimizu T (March 2005). "Identification of T cell death-associated gene 8 (TDAG8) as a novel acid sensing G-protein-coupled receptor". The Journal of Biological Chemistry. 280 (10): 9083–7. doi:10.1074/jbc.M407832200. PMID 15618224.
14. Yang L, Sanderlin E, Justus C, Krewson E (2 March 2015). "Emerging roles for the pH-sensing G protein-coupled receptors in response to acidotic stress". Cell Health and Cytoskeleton. 2015 (7): 99–109. doi:10.2147/CHC.S60508.
15. Yang L, Sanderlin E, Justus C, Krewson E (2 March 2015). "Emerging roles for the pH-sensing G protein-coupled receptors in response to acidotic stress". Cell Health and Cytoskeleton. 2015 (7): 99–109. doi:10.2147/CHC.S60508.
16. Ihara Y, Kihara Y, Hamano F, Yanagida K, Morishita Y, Kunita A, Yamori T, Fukayama M, Aburatani H, Shimizu T, Ishii S (October 2010). "The G protein-coupled receptor T-cell death-associated gene 8 (TDAG8) facilitates tumor development by serving as an extracellular pH sensor". Proceedings of the National Academy of Sciences of the United States of America. 107 (40): 17309–14. doi:10.1073/pnas.1001165107. PMC 2951433. PMID 20855608.
17. Onozawa Y, Fujita Y, Kuwabara H, Nagasaki M, Komai T, Oda T (2012). "Activation of T cell death-associated gene 8 regulates the cytokine production of T cells and macrophages in vitro". European Journal of Pharmacology. 683 (1–3): 325–31. doi:10.1016/j.ejphar.2012.03.007. PMID 22445881.
18. Nagasaka A, Mogi C, Ono H, Nishi T, Horii Y, Ohba Y, Sato K, Nakaya M, Okajima F, Kurose H (August 2017). "The proton-sensing G protein-coupled receptor T-cell death-associated gene 8 (TDAG8) shows cardioprotective effects against myocardial infarction". Scientific Reports. 7 (1): 7812. doi:10.1038/s41598-017-07573-2. PMC 5552703. PMID 28798316.
19. Ail D, Rüfenacht V, Caprara C, Samardzija M, Kast B, Grimm C (August 2015). "Increased expression of the proton-sensing G protein-coupled receptor Gpr65 during retinal degeneration". Neuroscience. 301: 496–507. doi:10.1016/j.neuroscience.2015.06.039. PMID 26117715.
20. Williams EK, Chang RB, Strochlic DE, Umans BD, Lowell BB, Liberles SD (2016). "Sensory Neurons that Detect Stretch and Nutrients in the Digestive System". Cell. 166 (1): 209–21. doi:10.1016/j.cell.2016.05.011. PMC 4930427. PMID 27238020.
21. Vollmer LL, Schmeltzer SN, Ahlbrand R, Sah R (October 2015). "A potential role for the acid-sensing T cell death associated gene-8 (TDAG8) receptor in depression-like behavior". Physiology & Behavior. 150: 78–82. doi:10.1016/j.physbeh.2015.03.012. PMC 4546899. PMID 25770699.
22. Choi JW, Lee SY, Choi Y (February 1996). "Identification of a putative G protein-coupled receptor induced during activation-induced apoptosis of T cells". Cellular Immunology. 168 (1): 78–84. doi:10.1006/cimm.1996.0051. PMID 8599842.

Further reading

• Sin WC, Zhang Y, Zhong W, Adhikarakunnathu S, Powers S, Hoey T, An S, Yang J (August 2004). "G protein-coupled receptors GPR4 and TDAG8 are oncogenic and overexpressed in human cancers". Oncogene. 23 (37): 6299–303. doi:10.1038/sj.onc.1207838. PMID 15221007.
• Radu CG, Nijagal A, McLaughlin J, Wang L, Witte ON (February 2005). "Differential proton sensitivity of related G protein-coupled receptors T cell death-associated gene 8 and G2A expressed in immune cells". Proceedings of the National Academy of Sciences of the United States of America. 102 (5): 1632–7. doi:10.1073/pnas.0409415102. PMC 545089. PMID 15665078.