The CB1 cannabinoid receptor is coupled to the activation of c-Jun N-terminal kinase

Cannabinoids exert most of their effects through the CB1 receptor. This G-p rotein-coupled receptor has been shown to be functionally coupled to inhibi tion of adenylyl cyclase, modulation of ion channels, and activation of ext racellular signal-regulated kinase. Using Chinese hamster ovary cells stabl y transfected with the CB1 receptor cDNA, we show here that Delta(9)-tetrah ydrocannabinol (THC), the major active component of marijuana, induces the activation of c-Jun N-terminal kinase (JNK). Western blot analysis showed t hat both JNK-1 and JNK-2 were stimulated by THC. The effect of THC was also exerted by endogenous cannabinoids (anandamide and 2-arachidonoylglycerol) and synthetic cannabinoids (CP-55,940, HU-210, and methanandamide), and wa s prevented by the selective CB1 antagonist SR141716. Pertussis toxin, wort mannin, and a Ras farnesyltransferase inhibitor peptide blocked, whereas ma stoparan mimicked, the CB1 receptor-evoked activation of JNK, supporting th e involvement of a G(i)/G(o)-protein, phosphoinositide 3'-kinase and Ras. T HC-induced JNK stimulation was prevented by tyrphostin AG1296, pointing to the implication of platelet-derived growth factor receptor transactivation, and was independent of ceramide generation. Experiments performed with sev eral types of neural cells that endogenously express the CB1 receptor sugge sted that long-term JNK activation may be involved in THC-induced cell deat h. The CB1 cannabinoid receptor was also shown to be coupled to the activat ion of p38 mitogen-activated protein kinase. Data indicate that activation of JNK and p38 mitogen-activated protein kinase may be responsible for some of the cellular responses elicited by the CB1 cannabinoid receptor.