GPR65

GPR65
Identifiers
Aliases	GPR65, TDAG8, hTDAG8, G protein-coupled receptor 65
External IDs	OMIM: 604620; MGI: 108031; HomoloGene: 2675; GeneCards: GPR65; OMA:GPR65 - orthologs
Gene location (Human) Chr. Chromosome 14 (human) Band 14q31.3 Start 88,005,135 bp End 88,014,811 bp
Gene location (Mouse) Chr. Chromosome 12 (mouse) Band 12|12 E Start 98,234,894 bp End 98,242,903 bp
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in white blood cell mononuclear cell monocyte periodontal fiber granulocyte blood bone marrow appendix trabecular bone spleen Top expressed in granulocyte stroma of bone marrow spleen lymph node thymus mesenteric lymph nodes blood dermis pharynx subcutaneous adipose tissue More reference expression data BioGPS More reference expression data
Gene ontology Molecular function G protein-coupled receptor activity signal transducer activity Cellular component integral component of membrane plasma membrane integral component of plasma membrane membrane intracellular anatomical structure Biological process multicellular organism development actin cytoskeleton reorganization immune response positive regulation of stress fiber assembly 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: 98.23 – 98.24 Mb PubMed search
Wikidata
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Psychosine receptor is a G protein-coupled receptor (GPCR) protein that in humans is encoded by the GPR65 gene. GPR65 is also referred to as TDAG8.

Function

Psychosine Receptor

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

pH Sensing

Wang et al. was the first to determine that GPR65 senses extracellular pH. Levels of cyclic AMP (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.

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. Because pH plays a prominent role in several biological systems, such as in the immune, cardiovascular, respiratory, renal, and nervous systems, a the ability of GPR65 to sense pH can modulate several cellular functions in various processes.

GPR65's ability to sense pH plays a prominent role in tumor development. GPR65 is highly expressed in a variety of human tumors. Seeing that 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.

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. 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 aptly named TDAG8, or T Cell Death Associated Gene 8.

See also

• Proton-sensing G protein-coupled receptors

Further reading

• 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.
• 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.
• 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.{{cite journal}}: CS1 maint: unflagged free DOI (link)
• 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.{{cite journal}}: CS1 maint: unflagged free DOI (link)
• 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.