Signal transduction via cannabinoid receptors

Abstract

The endocannabinoids anandamide and 2-arachidonoylglycerol are lipid mediators that signal via CB(1) and CB(2) cannabinoid receptors and Gi/o-proteins to inhibit adenylyl cyclase and stimulate mitogen-activated protein kinase. In the brain, CB(1) receptors interact with opioid receptors in close proximity, and these receptors may share G-proteins and effector systems. In the striatum, CB(1) receptors function in coordination with D(1) and D(2) dopamine receptors, and combined stimulation of CB(1)-D(2) receptor heteromeric complexes promotes a unique interaction to stimulate cAMP production. CB(1) receptors also trigger growth factor receptor signaling cascades in cells by engaging in cross-talk or interreceptor signal transmission with the receptor tyrosine kinase (RTK) family. Mechanisms for CB(1) receptor-RTK transactivation can include stimulation of signal transduction pathways regulated by second messengers such as phospholipase C, metalloprotease cleavage of membrane-bound precursor proteins such as epidermal growth factor which activate RTKs, RTK autophosphorylation, and recruitment of non-receptor tyrosine kinases. CB(1) and CB(2) receptors are expressed in peripheral tissues including liver and adipose tissue, and are induced in pathological conditions. Novel signal transduction resulting from endocannabinoid regulation of AMP-regulated kinase and peroxisome proliferator-activated receptors have been discovered from studies of hepatocytes and adipocytes. It can be predicted that drug discovery of the future will be based upon these novel signal transduction mechanisms for endocannabinoid mediators.

Fig. 1. Putative mechanisms of cross-talk between the CB₁ receptor and RTKs in neurons

(A) The synthetic CB₁ receptor agonist desacetyllevonantradol (DALN) potentiates Ca²⁺ influx in N18TG2 neuroblastoma cells via CB₁ receptor-mediated transactivation of the VEGF receptor [–89]. Agonist-stimulated CB₁ receptors interact with Gi/o to release Gβγ, which activate PI-3K, thereby promoting Raf-mediated ERK1/2 activation. By this scenario, Ca²⁺ enters the cell following CB₁ receptor-mediated ERK1/2 modulation of voltage-gated Ca²⁺ channel activity. Activated PKC could stimulate the MAPK cascade by phosphorylating Raf or by stimulating a metalloprotease that catalyzes production of VEGF (or other growth factor proteins) to activate RTKs. The transactivated VEGF receptor might also activate the MAPK cascade and further potentiate Ca²⁺ influx into neuronal cells. (B) The CB₁ receptor mediates Src kinase-dependent TrkB RTK transactivation in neurons (see text).