GPR55 is a cannabinoid receptor that increases intracellular calcium and inhibits M current

The CB₁ cannabinoid receptor mediates many of the psychoactive effects of Δ⁹THC, the principal active component of cannabis. However, ample evidence suggests that additional non-CB₁/CB₂ receptors may contribute to the behavioral, vascular, and immunological actions of Δ⁹THC and endogenous cannabinoids. Here, we provide further evidence that GPR55, a G protein-coupled receptor, is a cannabinoid receptor. GPR55 is highly expressed in large dorsal root ganglion neurons and, upon activation by various cannabinoids (Δ⁹THC, the anandamide analog methanandamide, and JWH015) increases intracellular calcium in these neurons. Examination of its signaling pathway in HEK293 cells transiently expressing GPR55 found the calcium increase to involve G_q, G₁₂, RhoA, actin, phospholipase C, and calcium release from IP₃R-gated stores. GPR55 activation also inhibits M current. These results establish GPR55 as a cannabinoid receptor with signaling distinct from CB₁ and CB₂.