Abstract
Cannabinoids exert most of their effects through the CB1 receptor. This G-protein-coupled receptor has been shown to be functionally coupled to inhibition of adenylyl cyclase, modulation of ion channels, and activation of extracellular signal-regulated kinase. Using Chinese hamster ovary cells stably transfected with the CB1 receptor cDNA, we show here that Δ9-tetrahydrocannabinol (THC), the major active component of marijuana, induces the activation of c-Jun N-terminal kinase (JNK). Western blot analysis showed that 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 was prevented by the selective CB1 antagonist SR141716. Pertussis toxin, wortmannin, and a Ras farnesyltransferase inhibitor peptide blocked, whereas mastoparan mimicked, the CB1receptor-evoked activation of JNK, supporting the involvement of a Gi/Go-protein, phosphoinositide 3′-kinase and Ras. THC-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 several types of neural cells that endogenously express the CB1 receptor suggested that long-term JNK activation may be involved in THC-induced cell death. The CB1 cannabinoid receptor was also shown to be coupled to the activation 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.
Footnotes
- Received January 10, 2000.
- Accepted June 19, 2000.
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Send reprint requests to: Dr. Manuel Guzmán, Department of Biochemistry and Molecular Biology I, School of Biology, Complutense University, 28040 Madrid, Spain. E-mail:mgp{at}solea.quim.ucm.es
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This study was supported by grants from Comisión Interministerial de Ciencia y Tecnologı́a (PM 98/0079) and Comunidad Autónoma de Madrid (CAM 08.5/0017/98).
- The American Society for Pharmacology and Experimental Therapeutics
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