Biology:GPR65

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Short description: Protein-coding gene in the species Homo sapiens


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

Psychosine receptor is a G protein-coupled receptor (GPCR) protein that in humans is encoded by the GPR65 gene.[1][2] GPR65 is also referred to as TDAG8.

Species, tissue, and subcellular distribution

GPR65 (TDAG8) is primarily expressed in lymphoid tissues (spleen, lymph nodes, thymus, and leukocytes),[3] 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.[4] However, the specific binding of psychosine to GPR65 has been contested as the reported ligand binding did not satisfy the appropriate pharmacological criteria.[5]

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.[6] 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.[7]

pH sensing

GPR65 senses extracellular pH.[8] 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.[9]

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.[10] 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.[11]

GPR65's ability to sense pH plays a prominent role in tumor development.[12] 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.[13]

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.[14]

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.[15]

Gastrointestinal

Vagal afferents expressing GPR65 innervate intestinal villi. These GPR65-expressing vagal afferents detect nutrients in the intestinal lumen and also slow gut motility.[16]

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.[17]

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.[18] 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

References

  1. ↑ "Cloning, characterization, and mapping of human homolog of mouse T-cell death-associated gene". DNA and Cell Biology 17 (6): 493–500. June 1998. doi:10.1089/dna.1998.17.493. PMID 9655242. 
  2. ↑ "Entrez Gene: GPR65 G protein-coupled receptor 65". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=8477. 
  3. ↑ "Identification of a putative G protein-coupled receptor induced during activation-induced apoptosis of T cells". Cellular Immunology 168 (1): 78–84. February 1996. doi:10.1006/cimm.1996.0051. PMID 8599842. 
  4. ↑ "Identification of a molecular target of psychosine and its role in globoid cell formation". The Journal of Cell Biology 153 (2): 429–34. April 2001. doi:10.1083/jcb.153.2.429. PMID 11309421. 
  5. ↑ "Discovery of new G protein-coupled receptors for lipid mediators". Journal of Lipid Research 45 (3): 410–8. March 2004. doi:10.1194/jlr.R300006-JLR200. PMID 14657204. 
  6. ↑ "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. May 2012. doi:10.1016/j.ejphar.2012.03.007. PMID 22445881. 
  7. ↑ "Allosteric ligands for the pharmacologically dark receptors GPR68 and GPR65". Nature 527 (7579): 477–83. 2015. doi:10.1038/nature15699. PMID 26550826. Bibcode: 2015Natur.527..477H. 
  8. ↑ "TDAG8 is a proton-sensing and psychosine-sensitive G-protein-coupled receptor". The Journal of Biological Chemistry 279 (44): 45626–33. October 2004. doi:10.1074/jbc.M406966200. PMID 15326175. 
  9. ↑ "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. March 2005. doi:10.1074/jbc.M407832200. PMID 15618224. http://www.jbc.org/content/280/10/9083.long. 
  10. ↑ "Emerging roles for the pH-sensing G protein-coupled receptors in response to acidotic stress". Cell Health and Cytoskeleton 2015 (7): 99–109. 2 March 2015. doi:10.2147/CHC.S60508. 
  11. ↑ "Emerging roles for the pH-sensing G protein-coupled receptors in response to acidotic stress". Cell Health and Cytoskeleton 2015 (7): 99–109. 2 March 2015. doi:10.2147/CHC.S60508. 
  12. ↑ "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. October 2010. doi:10.1073/pnas.1001165107. PMID 20855608. Bibcode: 2010PNAS..10717309I. 
  13. ↑ "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. 2012. doi:10.1016/j.ejphar.2012.03.007. PMID 22445881. 
  14. ↑ "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. August 2017. doi:10.1038/s41598-017-07573-2. PMID 28798316. Bibcode: 2017NatSR...7.7812N. 
  15. ↑ "Increased expression of the proton-sensing G protein-coupled receptor Gpr65 during retinal degeneration". Neuroscience 301: 496–507. August 2015. doi:10.1016/j.neuroscience.2015.06.039. PMID 26117715. 
  16. ↑ "Sensory Neurons that Detect Stretch and Nutrients in the Digestive System". Cell 166 (1): 209–21. 2016. doi:10.1016/j.cell.2016.05.011. PMID 27238020. 
  17. ↑ "A potential role for the acid-sensing T cell death associated gene-8 (TDAG8) receptor in depression-like behavior". Physiology & Behavior 150: 78–82. October 2015. doi:10.1016/j.physbeh.2015.03.012. PMID 25770699. 
  18. ↑ "Identification of a putative G protein-coupled receptor induced during activation-induced apoptosis of T cells". Cellular Immunology 168 (1): 78–84. February 1996. doi:10.1006/cimm.1996.0051. PMID 8599842. 

Further reading



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