Abstract

The CB₁ cannabinoid receptor (CB₁R) is the major cannabinoid receptor in neuronal cells and the brain, but it also occurs in endocrine cells and other peripheral tissues. CB₁R is a member of the superfamily of G-protein-coupled receptors (GPCRs), which are characterized by seven transmembrane helices. The major mediators of CB₁R are the G proteins of the G_i/o family, which inhibit adenylyl cyclases in most tissues and cells, and regulate ion channels, including calcium and potassium ion channels. Regulation of ion channels is an important component of neurotransmission modulation by endogenous cannabinoid compounds released in response to depolarization and Ca²⁺-mobilizing hormones. However, evidence exists that CB₁Rs can also stimulate adenylyl cyclase via G_s, induce receptor-mediated Ca²⁺ fluxes and stimulate phospholipases in some experimental models. Stimulation of CB₁R also leads to phosphorylation and activation of mitogen-activated protein kinases (MAPK), such as p42/p44 MAPK, p38 MAPK and c-Jun N-terminal kinase, which can regulate nuclear transcription factors. Activated and phosphorylated CB₁Rs also associate with β-arrestin molecules, which can induce the formation of signalling complexes and participate in the regulation of GPCR signalling. Recent data also suggest that CB₁Rs can form homo- and heterodimers/oligomers, and the altered pharmacological properties of these receptor complexes may explain the pharmacological differences observed in various tissues.