Contents:
- Gene and Protein Information
- Previous and Unofficial Names
- Database Links
- Natural/Endogenous Ligands
- Agonists
- Antagonists
- Immunopharmacology Comments
- Immuno Cell Type Associations
- Transduction Mechanisms
- Tissue Distribution
- Expression Datasets
- Functional Assays
- Physiological Functions
- Physiological Consequences of Altering Gene Expression
- Phenotypes, Alleles and Disease Models
- Gene Expression and Pathophysiology
- Biologically Significant Variants
- General Comments
- References
- Contributors
- How to cite this page
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 | 337 | 14q31.3 | GPR65 | G protein-coupled receptor 65 | 10 |
| Mouse | 7 | 337 | 12 E | Gpr65 | G-protein coupled receptor 65 | |
| Rat | 7 | 337 | 6q32 | Gpr65 | G-protein coupled receptor 65 | |
| Previous and Unofficial Names |
| Dig1 | Gpcr25 | Psychosine receptor | TDAG8 | T cell death associated protein 8 |
| Database Links |
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| Specialist databases | |
| GPCRdb | psyr_human (Hs), psyr_mouse (Mm) |
| Other databases | |
| Alphafold | Q8IYL9 (Hs), Q61038 (Mm) |
| ChEMBL Target | CHEMBL3714081 (Hs) |
| Ensembl Gene | ENSG00000140030 (Hs), ENSMUSG00000021886 (Mm), ENSRNOG00000065590 (Rn) |
| Entrez Gene | 8477 (Hs), 14744 (Mm), 299242 (Rn) |
| Human Protein Atlas | ENSG00000140030 (Hs) |
| KEGG Gene | hsa:8477 (Hs), mmu:14744 (Mm), rno:299242 (Rn) |
| OMIM | 604620 (Hs) |
| Pharos | Q8IYL9 (Hs) |
| RefSeq Nucleotide | NM_003608 (Hs), NM_008152 (Mm), NM_001106751 (Rn) |
| RefSeq Protein | NP_003599 (Hs), NP_032178 (Mm), NP_001100221 (Rn) |
| UniProtKB | Q8IYL9 (Hs), Q61038 (Mm) |
| Wikipedia | GPR65 (Hs) |
| Natural/Endogenous Ligands |
| Protons |
| Agonist Comments | ||
| It was initially believed that psychosine and other lysolipids acted at human GPR65 to inhibit of forskolin-stimulated cAMP formation in a concentration- dependent manner [6]. However, GPR4, GPR 65, GPR68 and GPR132 are now thought to function as proton-sensing receptors detecting acidic pH [2,22]; lysolipids may actually be antagonists at GPR65 [22,24]. BTB09089 has been reported to be an agonist of GPR65 [17]. |
| Antagonist Comments | ||
| Psychosine related lysoslipids behave as antagonists against proton-sensing GPR65 [24]. |
| Immunopharmacology Comments |
| Tha expression profile of GPR65 suggests an immunological role. In addition, disruption of GPR65 expression leads to reduced eosinophilia in models of allergic airway disease [9]. |
| Cell Type Associations | ||||||
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| Primary Transduction Mechanisms
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| Transducer | Effector/Response |
| Gs family | Adenylyl cyclase stimulation |
| Comments: GPR65 response to psychosine was not blocked by pre-treatment of RH7777 cells with pertussis toxin, suggesting the involvement of PTX-insensitive G proteins, perhaps Gαs. Proton stimulation of the receptor causes cAMP accumulation [7,19]. This proton-receptor interaction may be mediated by Gs proteins [24]. GPR65 mediates, at least partly, inhibition of proinflammatory cytokine production induced by the extracellular acidification through Gs protein/cAMP/PKA. | |
| References: 7,15,19,24 | |
| Tissue Distribution
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| Tissue Distribution Comments | ||||||||
| GPR65 is overexpressed by more than 5x in a range of human cancer tissues (kidney, ovarian, colon, breast) screened using quantitative fluorescence-based real-time PCR [23]. Enhanced green fluorescent protein reporter has been knocked into the disrupted GPR65 locus to allow the analysis of TDAG8 expression in living cells [18]. GPR65 is expressed in nociceptors of the lumbar dorsal root ganglion in mice (RT-PCR) [5]. Receptor expression is increased in eosinophils in murine models of allergic asthma and human populations during acute asthma exacerbations [9]. | ||||||||
| Expression Datasets |
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| Functional Assays
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| Functional Assay Comments | ||||||||||
| Cell-based fluorescence imaging system successfully monitored the internalization of the proton-sensing GPR65 [4]. |
| Physiological Functions
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| Physiological Functions Comments | ||||||||
| Receptor mediated increased intracellular cAMP concentration may mediate the acidic pH-induced inhibition of superoxide anion production [16]. | ||||||||
| Physiological Consequences of Altering Gene Expression
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| Physiological Consequences of Altering Gene Expression Comments | ||||||||||
| Gene profiling of GPR65 indicates that mRNA is down regulated in leukemic cells overexpressing growth factor independence 1B gene [8]. | ||||||||||
| Phenotypes, Alleles and Disease Models
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Mouse data from MGI | ||||||||||||||||||||||||||||||||||||
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| Gene Expression and Pathophysiology Comments | |
| Chromosomal location and tissue distribution implicates GPR65 in T-cell-associated diseases [10]. Association with the ligand psychosine indicates a role for the receptor in globoid cell leukodystrophy [6]. Receptor overexpression in a range of human cancer tissues suggest contribution to tumor development [23]. Genome-wide association and fine mapping of genetic loci indicates Gpr65 in predisposition to colon carcinogenesis in mice [11]. |
| Biologically Significant Variants
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| General Comments |
| GPR65 may be a Stat3alpha gene target [20]. |
References
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2. Davenport AP, Alexander SP, Sharman JL, Pawson AJ, Benson HE, Monaghan AE, Liew WC, Mpamhanga CP, Bonner TI, Neubig RR et al.. (2013) International Union of Basic and Clinical Pharmacology. LXXXVIII. G protein-coupled receptor list: recommendations for new pairings with cognate ligands. Pharmacol Rev, 65 (3): 967-86. [PMID:23686350]
3. Duong CQ, Bared SM, Abu-Khader A, Buechler C, Schmitz A, Schmitz G. (2004) Expression of the lysophospholipid receptor family and investigation of lysophospholipid-mediated responses in human macrophages. Biochim Biophys Acta, 1682 (1-3): 112-9. [PMID:15158762]
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5. Huang CW, Tzeng JN, Chen YJ, Tsai WF, Chen CC, Sun WH. (2007) Nociceptors of dorsal root ganglion express proton-sensing G-protein-coupled receptors. Mol Cell Neurosci, 36 (2): 195-210. [PMID:17720533]
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14. McGuire J, Herman JP, Ghosal S, Eaton K, Sallee FR, Sah R. (2009) Acid-sensing by the T cell death-associated gene 8 (TDAG8) receptor cloned from rat brain. Biochem Biophys Res Commun, 386 (3): 420-5. [PMID:19501050]
15. Mogi C, Tobo M, Tomura H, Murata N, He XD, Sato K, Kimura T, Ishizuka T, Sasaki T, Sato T, Kihara Y, Ishii S, Harada A, Okajima F. (2009) Involvement of proton-sensing TDAG8 in extracellular acidification-induced inhibition of proinflammatory cytokine production in peritoneal macrophages. J Immunol, 182 (5): 3243-51. [PMID:19234222]
16. Murata N, Mogi C, Tobo M, Nakakura T, Sato K, Tomura H, Okajima F. (2009) Inhibition of superoxide anion production by extracellular acidification in neutrophils. Cell Immunol, 259 (1): 21-6. [PMID:19539899]
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. Eur J Pharmacol, 683 (1-3): 325-31. [PMID:22445881]
18. Radu CG, Cheng D, Nijagal A, Riedinger M, McLaughlin J, Yang LV, Johnson J, Witte ON. (2006) Normal immune development and glucocorticoid-induced thymocyte apoptosis in mice deficient for the T-cell death-associated gene 8 receptor. Mol Cell Biol, 26 (2): 668-77. [PMID:16382156]
19. Radu CG, Nijagal A, McLaughlin J, Wang L, Witte ON. (2005) Differential proton sensitivity of related G protein-coupled receptors T cell death-associated gene 8 and G2A expressed in immune cells. Proc Natl Acad Sci USA, 102 (5): 1632-7. [PMID:15665078]
20. Redell MS, Tsimelzon A, Hilsenbeck SG, Tweardy DJ. (2007) Conditional overexpression of Stat3alpha in differentiating myeloid cells results in neutrophil expansion and induces a distinct, antiapoptotic and pro-oncogenic gene expression pattern. J Leukoc Biol, 82 (4): 975-85. [PMID:17634277]
21. Ryder C, McColl K, Zhong F, Distelhorst CW. (2012) Acidosis Promotes Bcl-2 Family-mediated Evasion of Apoptosis: INVOLVEMENT OF ACID-SENSING G PROTEIN-COUPLED RECEPTOR GPR65 SIGNALING TO MEK/ERK. J Biol Chem, 287 (33): 27863-75. [PMID:22685289]
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