G2A (GPR132)

The family of proton-sensing G-protein coupled receptors (GPCRs) has first been described by Ludwig et al. in 2003 and consists of four members that belong to the class A orphan GPCRs: GPR4, TDAG8 (GPR65), OGR1 (GPR68), and G2A (GPR132).

G2A (GPR132), the abbreviation, G2A, is a stress-induced receptor and that its expression is enhanced upon DNA damage, leading to cell cycle arrest in the G2/M phase. The term: “G2-cell cycle arrest” was chosen as a name for the receptor. G2A is mainly expressed in leukocytes and seems to be responsible for the migration of macrophages. Interestingly, G2A is also expressed in peripheral sensory neurons that co-express the TRPV1 channel. In these neurons, G2A seems to communicate with TRPV1 and enhance its activity via protein kinase C during oxaliplatin-induced neuropathic pain.

G2A is the least sensitive to protons among four receptors, and its activation leads to the production of inositol trisphosphate (IP3) through G_q activation. It is activated at pH 7.4, with the response increasing monotonously as the pH decreases from 8.2 to 6.6. G2A is proposed as a receptor for lipids, especially lysophospholipids. Which was later retracted. It seems that lysophospholipids are not direct activators but are involved in the trafficking of G2A to the plasma membrane. Lysophospholipids also act as chemoattractants for T-cell migration through G2A. Another study found that LPC may be a weak antagonist of G2A, but the required concentrations are high (>10 µM). The strongest G2A activation was caused by linoleic acid metabolite 9S-HODE (EC₅₀: ~0.5 µM) in a heterologous expression system. A recent study also identified N-palmitoylglycine and N-linoleoylglycine as G2A activators with similar potency to 9-HODE, reinforcing the concept of G2A as a receptor for signaling lipids rather than protons and acidification. In the same study, the angiotensin-II type I receptor antagonist telmisartan and its analogue GSK1820795A were identified as potent G2A inhibitors.

In the tumor microenvironment, G2A has been suggested to silence tumor-associated macrophages (TAMs). Breast tumor cells produce lactate, which can activate G2A in TAMs non-aggressive M2-like state and enhancing tumor growth. G2A may thus be a novel target for breast cancer.

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