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

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Abstract
The CB 1 cannabinoid receptor mediates many of the psychoactive effects of Δ 9 THC, the principal active component of cannabis. However, ample evidence suggests that additional non-CB 1 /CB 2 receptors may contribute to the behavioral, vascular, and immunological actions of Δ 9 THC 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 (Δ 9 THC, 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 , G 12 , RhoA, actin, phospholipase C, and calcium release from IP 3 R-gated stores. GPR55 activation also inhibits M current. These results establish GPR55 as a cannabinoid receptor with signaling distinct from CB 1 and CB 2 .