GPR65, also called TDAG8 (T-cell death associated gene 8 protein), is a pH-sensing G-protein coupled receptor (GPCR) activated by acidic extracellular pH through the protonation of several histidine residues in the receptor’s sequence. GPR65 is involved in cancer cell metastasis and proliferation, immune cell function, inflammation, and blood vessel formation¹.

Human GPR65 gene has been mapped to a location that is associated with T cell lymphoma and leukemia abnormalities.

GPR65 is primarily expressed in immune cells and leukocyte-rich tissues such as circulating peripheral leukocytes, spleen, thymus, and tonsils. Expression is also detected pain relevant loci such as the dorsal root ganglia neurons and particularly small diameter neurons responsible for nociception^1,2.

GPR65 has the ability to affect tumor development and growth. Overexpression of GPR65 in Lewis lung carcinoma cells increases tumor growth in mice and may facilitate resistance to acidosis-mediated cell death in vitro through protein kinase A (PKA) and ERK related pathways¹.

Knockdown of GPR65 in NCI-H460 human non-small cell lung cancer cells decreases cell survival in acidic condition. Another study shows that activation of GPR65 by acidosis can promote evasion of cell apoptosis under glutamine starvation and its overexpression has been reported to transform immortalized mammary epithelial cells¹.