GPR65

Official Full Name

G protein-coupled receptor 65

Organism

Homo sapiens

GeneID

8477

Background

Enables G protein-coupled receptor activity. Involved in several processes, including activation of GTPase activity; positive regulation of stress fiber assembly; and response to acidic pH. Located in plasma membrane. [provided by Alliance of Genome Resources, Feb 2025]

Synonyms

TDAG8; hTDAG8;

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Detailed Information

The GPR65 gene encodes G protein-coupled receptor 65 (GPR65), also known as T-cell death-associated gene 8 (TDAG8). GPR65 is a pH-sensitive receptor belonging to the class A rhodopsin-like G protein-coupled receptor (GPCR) family, characterized as a seven-transmembrane protein that senses extracellular pH changes and transduces them into intracellular signals. Initially identified as a receptor capable of binding glycosphingolipids, its most prominent feature is activation under mildly acidic conditions, reflecting the extracellular pH dependence of its function. GPR65 is highly expressed in immune cells, including macrophages, microglia, neutrophils, and T lymphocytes, with expression regulated by cellular activation state and cytokine milieu, suggesting a role in fine-tuning immune responses.

Biological Significance

GPR65 functions as a sensor of acidic microenvironments, linking local tissue metabolic status to immune cell activity. Under pathological conditions such as inflammation, ischemia, or tumor growth, tissue acidification occurs due to enhanced anaerobic glycolysis and lactate accumulation. GPR65 detects this pH decrease and, upon activation, signals through coupled Gαs and Gα12/13 pathways, modulating various cellular functions. In immune responses, GPR65 activation helps maintain lysosomal integrity and supports macrophage phagocytic activity, indicating a key role in host defense against intracellular pathogens.

Figure 1. Some major Gαs-coupled GPCRs in immune cells, including GPR65, GPR174, and A2aR, activate adenylate cyclase to elevate cAMP levels. (Robert R, et al., 2018)

Moreover, GPR65 may regulate activation-induced T-cell death or differentiation, controlling the magnitude and duration of immune responses and preventing tissue damage from excessive immune activation. Genetic studies have linked GPR65 polymorphisms to susceptibility to autoimmune diseases such as multiple sclerosis, rheumatoid arthritis, and inflammatory bowel disease, with gain-of-function variants associated with reduced disease risk. This underscores GPR65's protective role in immune tolerance, likely through mechanisms that include suppressing excessive inflammation, promoting regulatory T-cell function, or inducing effector T-cell apoptosis. Collectively, GPR65 acts as an immune homeostasis regulator, enabling immune cells to adjust functional output based on the metabolic state of their microenvironment.

Clinical Relevance

Clinically, GPR65 is relevant in both autoimmune diseases and the tumor immune microenvironment. As a disease susceptibility gene, it is an attractive therapeutic target. Protective alleles (e.g., I231L) enhance receptor function and reduce disease risk, suggesting that selective GPR65 agonists could mimic this effect to suppress hyperactive immune responses in conditions such as multiple sclerosis or inflammatory bowel disease. Because these agonists are activated in acidic microenvironments, they offer potential targeted therapy while minimizing systemic immunosuppression.

In oncology, the acidic tumor microenvironment provides a unique context for GPR65 function. Persistent exposure of tumor-infiltrating immune cells to acidic conditions may influence anti-tumor immunity. GPR65 activation can potentially inhibit effector T-cell and NK cell activity, or promote polarization of immunosuppressive regulatory T cells and M2 macrophages, facilitating tumor immune evasion. In such cases, GPR65 antagonists could enhance immune checkpoint therapies by relieving suppression. Conversely, GPR65 signaling may sometimes limit tumor-associated inflammation, highlighting the complexity of its role, which depends on tumor type and immune cell composition. Therefore, understanding GPR65 signaling in specific immune cell subsets and pathological microenvironments is critical for translating its biology into therapy. Currently, specific small-molecule modulators of GPR65 are under development, serving as tools to explore therapeutic potential and elucidate its complex biological functions.

References

Ihara Y, Kihara Y, Hamano F, et al. The G protein-coupled receptor T-cell death-associated gene 8 (TDAG8) facilitates tumor development by serving as an extracellular pH sensor. Proc Natl Acad Sci U S A. 2010;107(40):17309–17314.
Robert R, Mackay CR. Gαs-coupled GPCRs GPR65 and GPR174. Downers for immune responses. Immunol Cell Biol. 2018 Apr;96(4):341-343.

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