Cannabinoid signalling

After their discovery, the two known cannabinoid receptors, CB1 and CB2, have been the focus of research into the cellular signalling mechanisms of cannabinoids. The initial assessment, mainly derived from expression studies, was that cannabinoids, via Gi/o proteins, negatively modulate cyclic AMP levels, and activate inward rectifying K+ channels. Recent findings have complicated this assessment on different levels: (1) cannabinoids include a wide range of compounds with varying profiles of affinity and efficacy at the known CB receptors, and these profiles do not necessarily match their biological activity; (2) CB receptors appear to be intrinsically active and possibly coupled to more than one type of G protein; (3) CB receptor signalling mechanisms are diverse and dependent on the system studied; (4) cannabinoids have other targets than CB receptors. The aim of this mini review is to discuss the current literature regarding CB receptor signalling pathways. These include regulation of adenylyl cyclase, MAP kinase, intracellular Ca2+, and ion channels. In addition, actions of cannabinoids that are not mediated by CB1 or CB2 receptors are discussed.