Cannabinoid receptor signaling

The cannabinoid receptor family currently includes two types: CB1, characterized in neuronal cells and brain, and CB2, characterized in immune cells and tissues. CB1 and CB2 receptors are members of the superfamily of seven-transmembrane-spanning (7-TM) receptors, having a protein structure defined by an array of seven membrane-spanning helices with intervening intracellular loops and a C-terminal domain that can associate with G proteins. Cannabinoid receptors are associated with G proteins of the Gi/o family (Gi1, 2 and 3, and Go1 and 2). Signal transduction via Gi inhibits adenylyl cyclase in most tissues and cells, although signaling via Gs stimulates adenylyl cyclase in some experimental models. Evidence exists for cannabinoid receptor-mediated Ca2+ fluxes and stimulation of phospholipases A and C. Stimulation of CB1 and CB2 cannabinoid receptors leads to phosphorylation and activation of p42/p44 mitogen-activated protein kinase (MAPK), p38 MAPK and Jun N-terminal kinase (JNK) as signaling pathways to regulate nuclear transcription factors. The CB1 receptor regulates K+ and Ca2+ ion channels, probably via Go. Ion channel regulation serves as an important component of neurotransmission modulation by endogenous cannabinoid compounds released in response to neuronal depolarization. Cannabinoid receptor signaling via G proteins results from interactions with the second, third and fourth intracellular loops of the receptor. Desensitization of signal transduction pathways that couple through the G proteins probably entails phosphorylation of critical amino acid residues on these intracellular surfaces.