Signal transduction of the CB1 cannabinoid receptor

Abstract

The CB 1 cannabinoid receptor (CB 1 R) is the major cannabinoid receptor in neuronal cells and the brain, but it also occurs in endocrine cells and other peripheral tissues. CB 1 R is a member of the superfamily of G-protein-coupled receptors (GPCRs), which are characterized by seven transmembrane helices. The major mediators of CB 1 R 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 Ca 2C -mobilizing hormones. However, evidence exists that CB 1 Rs can also stimulate adenylyl cyclase via G s , induce receptor-mediated Ca 2C fluxes and stimulate phospholipases in some experimental models. Stimulation of CB 1 R 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 CB 1 Rs also associate with b-arrestin molecules, which can induce the formation of signalling complexes and participate in the regulation of GPCR signalling. Recent data also suggest that CB 1 Rs can form homo-and heterodimers/oligomers, and the altered pharmacological properties of these receptor complexes may explain the pharmacological differences observed in various tissues.

The Endocannabinoid/Endovanilloid N-Arachidonoyl Dopamine (NADA) and Synthetic Cannabinoid WIN55,212-2 Abate the Inflammatory Activation of Human Endothelial Cells

“…The canonical pathway activated downstream of CB 1 R/CB 2 R leads to the inhibition of protein kinase A (PKA) through the G i/o proteins (122). However, the PKA-dependent phosphorylation of TRPV1 augments its sensitization, and correspondingly, a reduction in PKA activity will lead to its inactivation, opposing the agonist activity of NADA at TRPV1 (123).…”

Mutations in the ‘DRY’ motif of the CB1 cannabinoid receptor result in biased receptor variants

“…The signaling pathways originating from CB 1 R are mediated mainly via heterotrimeric G i/o proteins, and include inhibition of cAMP production, activation of GIRK potassium channels, inhibition of Ca v calcium channels, and activation of MAPK cascades (Turu & Hunyady 2010). Moreover, CB 1 R shows basal G-protein activation and constitutive internalization under diverse cellular conditions (Leterrier et al 2006, McDonald et al 2007, Turu et al 2007.…”

Inhibitory signaling by CB1 receptors in smooth muscle mediated by GRK5/β-arrestin activation of ERK1/2 and Src kinase

“…Thus, unlike other Gi-coupled receptors in smooth muscle, CB1 receptors did not engage G␤␥ but signaled via GRK5/ ␤-arrestin activation of ERK1/2 and Src kinase: ERK1/2 accelerated inactivation of G␣q by RGS4, and Src kinase enhanced MLC phosphatase activity, leading to inhibition of ACh-stimulated contraction. beta arrestin; CB1 receptors; ERK1/2; GRK5; Src kinase THE PROPERTIES AND ROLE OF G protein-coupled cannabinoid receptors, CB 1 and CB 2 , have been extensively studied in their primary locations: the central and peripheral nervous system and the immune system, respectively (3,8,22,32). The location of CB 1 receptors in the brain (cerebral cortex, hippocampus, basal ganglia, amygdala, and cerebellum) correlates with the observed psychotropic effects of cannabinoids.…”