Cannabinoid receptor signaling pathways

Central nervous system responses to cannabis are believed to be primarily mediated by the CB1 receptor which preferentially couples to G i/o G proteins. Here, I show that CB1 activation by aminoalkylindole agonists increases intracellular calcium concentration by several hundred nanomolar in HEK 293 cells stably expressing CB1 and in cultured hippocampal neurons. The calcium increase is pertussis toxin insensitive, is mediated by Gq G proteins and phospholipase C, and results from calcium release from the ER via IP3Rs and RyRs. This result is the first to show that CB1 can be stabilized in a conformation that activates Gq signaling.; There is considerable evidence to suggest that cannabinoid receptors other than CB1 can mediate some of the physiological effects of cannabis and endocannabinoids. I have found that the orphan receptor GPR55 is an additional cannabinoid receptor. It is widely expressed in the brain and when transiently expressed in HEK 293 cells, is activated by some cannabinoid agonists to increase intracellular calcium via a signaling pathway that requires Gq, G12, PLC, Rho, and IP3Rs. GPR55 activation also inhibits M-type potassium current. The data indicate that GPR55 is a novel cannabinoid receptor that is likely to also play a role in the psychoactive effects of cannabis.