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

TLDR

CB1 mediates many psychoactive effects of Δ9 THC, yet evidence indicates that additional non‑CB1/CB2 receptors contribute to the behavioral, vascular, and immunological actions of Δ9 THC and endogenous cannabinoids. The study aims to provide further evidence that GPR55 is a cannabinoid receptor. In HEK293 cells expressing GPR55, activation triggers a Gq/G12/RhoA/actin/PLC‑dependent pathway that releases calcium from IP3R‑gated stores. GPR55 is highly expressed in large dorsal root ganglion neurons, where activation by Δ9 THC, anandamide analog, or JWH015 elevates intracellular calcium and inhibits M current, establishing it as a cannabinoid receptor with signaling distinct from CB1 and CB2.

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 .