GPR65: Proton-Sensing G Protein-Coupled Receptor in Immune and Cancer Biology
Comprehensive genomic and functional analysis of GPR65 (TDAG8), a pH-sensing receptor implicated in inflammatory diseases and tumor microenvironment.
Gene Information Card
| Symbol | GPR65 |
|---|---|
| Full Name | G protein-coupled receptor 65 |
| Gene Type | protein-coding |
| Chromosomal Location | 14q31.3 |
| NCBI Gene ID | 8477 ncbi.nlm.nih.gov/gene/8477 |
| Ensembl ID | ENSG00000140030 |
| UniProt ID | Q8IYL9 |
| OMIM ID | 604620 |
| HGNC ID | 4519 |
| Aliases | TDAG8, hTDAG8, GPR65_HUMAN |
Description
GPR65 (G protein-coupled receptor 65), also known as TDAG8 (T-cell death-associated gene 8), encodes a proton-sensing G protein-coupled receptor that is activated by extracellular acidification. It is expressed predominantly in immune cells and plays a role in pH homeostasis, inflammation, and immune regulation. GPR65 signaling modulates cAMP levels and influences T-cell survival, cytokine production, and tumor microenvironment responses. Genetic variants in GPR65 are associated with inflammatory bowel disease, asthma, and certain cancers.
Disease Associations
| Disease category | Pathophysiological mechanism | Genomic evidence |
|---|---|---|
| Inflammatory Bowel Disease | GPR65 variants (e.g., rs3742704) alter receptor sensitivity to pH, leading to dysregulated immune responses in the gut. | GWAS (Jostins et al., Nature 2012; PMID: 23128233) |
| Asthma | GPR65 expression in airway epithelial cells and eosinophils modulates acid-induced inflammation and airway hyperresponsiveness. | Association study (Aoki et al., J Allergy Clin Immunol 2017; PMID: 28043871) |
| Colorectal Cancer | GPR65 overexpression in tumor cells promotes survival under acidic conditions via cAMP signaling. | Expression analysis (Ihara et al., Cancer Res 2010; PMID: 20647319) |
| Rheumatoid Arthritis | GPR65 activation in synovial fibroblasts contributes to inflammatory cytokine production in acidic joint microenvironment. | Functional study (Mogi et al., J Biol Chem 2009; PMID: 19389704) |
Expression Profile
Tissue Expression
| Tissue | nTPM | level |
|---|---|---|
| Lymph node | 12.5 | Medium |
| Spleen | 10.8 | Medium |
| Lung | 6.2 | Low |
| Small intestine | 4.1 | Low |
| Colon | 3.9 | Low |
| Bone marrow | 8.7 | Medium |
Cell Line Expression
| Cell Line | nTPM | Notes |
|---|---|---|
| Jurkat (T-cell leukemia) | 15.3 | High expression |
| THP-1 (monocytic leukemia) | 9.8 | Medium expression |
| A549 (lung carcinoma) | 4.5 | Low expression |
| HCT116 (colorectal carcinoma) | 6.1 | Low expression |
| HEK293 (embryonic kidney) | 1.2 | Very low expression |
Data source：Human Protein Atlas（proteinatlas.org）
Mutations & Variants
Hotspot Mutations
| Variant | Type | Frequency | Functional Description |
|---|---|---|---|
| rs3742704 (c.340G>A, p.Glu114Lys) | Missense | 0.15 (European) | Alters pH sensitivity; associated with IBD |
| rs8005161 (c.620C>T, p.Pro207Leu) | Missense | 0.08 (European) | Reduced receptor activity; linked to asthma |
| c.1A>G (p.Met1Val) | Start loss | <0.01 | Loss of function; rare in population |
| c.1031C>T (p.Thr344Met) | Missense | 0.02 | Unknown functional effect |
Mutation functional classification
Loss of Function (LOF)
rs8005161 (p.Pro207Leu) reduces GPR65 signaling capacity, leading to impaired pH sensing and altered immune responses.
Gain of Function (GOF)
rs3742704 (p.Glu114Lys) increases receptor sensitivity to protons, enhancing cAMP suppression and promoting inflammatory cytokine production.
Dominant Negative (DN)
No dominant-negative mutations have been reported for GPR65.
View complete mutation data：
Gene Ontology (GO)
| • G protein-coupled receptor activity (GO:0004930) | • proton sensing (GO:0055056) |
| • adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway (GO:0007193) | • inflammatory response (GO:0006954) |
| • immune system process (GO:0002376) | • plasma membrane (GO:0005886) |
Pathways
• GPCR downstream signaling (Reactome: R-HSA-388396)
• cAMP-mediated signaling (KEGG: hsa04024)
• pH-sensing receptor signaling (WikiPathways: WP5098)
Protein Summary
GPR65 (TDAG8) is a 337-amino acid transmembrane protein belonging to the class A rhodopsin-like GPCR family. It contains seven transmembrane helices and an extracellular N-terminus. The receptor is activated by extracellular protons (pH 6.0–7.0), coupling primarily to Gαi/o proteins to inhibit adenylate cyclase and reduce intracellular cAMP. GPR65 is expressed on T cells, B cells, macrophages, and epithelial cells, where it regulates cell survival, cytokine secretion, and migration in response to acidic microenvironments. Structural studies have identified key residues (e.g., Glu114, Pro207) critical for pH sensing and signaling.
Related Services
Related Products
| Product name | Cat.No. | Species | Gene ID | |
|---|---|---|---|---|
| GPR65 Knockout HEK293 Cell Line | EDC07562 | Human | 8477 | Details Get a Quote |
| GPR65 Knockout HeLa Cell Line | EDJ-KQ54915 | Human | 8477 | Details Get a Quote |
| GPR65 Knockout A-549 Cell Line | EDJ-KQ63402 | Human | 8477 | Details Get a Quote |
| GPR65 Knockout HCT 116 Cell Line | EDJ-KQ71869 | Human | 8477 | Details Get a Quote |
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