The CB(1) cannabinoid receptor is coupled to the activation of c-Jun N-terminal kinase.
Cannabinoids exert most of their effects through the CB(1) 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 CB(1) receptor cDNA, we show here that Delta(9)-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 CB(1) antagonist SR141716. Pertussis toxin, wortmannin, and a Ras farnesyltransferase inhibitor peptide blocked, whereas mastoparan mimicked, the CB(1) receptor-evoked activation of JNK, supporting the involvement of a G(i)/G(o)-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 CB(1) receptor suggested that long-term JNK activation may be involved in THC-induced cell death. The CB(1) 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 CB(1) cannabinoid receptor.
Rueda
D
D
Department of Biochemistry and Molecular Biology I, School of Biology, Complutense University, Madrid, Spain.
Galve-Roperh
I
I
Haro
A
A
Guzmán
M
M
D000818:Animals; D016466:CHO Cells; D002186:Cannabinoids / Q000378:metabolism; D002518:Ceramides / Q000494:pharmacology; D006224:Cricetinae; D004789:Enzyme Activation; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000378:metabolism; D020962:Heterotrimeric GTP-Binding Proteins / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051381:Rats; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug / Q000378:metabolism*; D017479:Receptors, Platelet-Derived Growth Factor / Q000235:genetics / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases; D018631:ras Proteins / Q000378:metabolism
D002186:Cannabinoids; D002518:Ceramides; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug; D019869:Phosphatidylinositol 3-Kinases; D017479:Receptors, Platelet-Derived Growth Factor; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; D020962:Heterotrimeric GTP-Binding Proteins; D018631:ras Proteins