IN-VITRO ACTIVATION OF BRAIN PROTEIN-KINASE-C BY THE CANNABINOIDS

The cannabinoids have been shown to affect both membrane lipid orderin g and the activities of several membrane-associated proteins. We have investigated the effects of the cannabinoids on protein kinase C, a li pid-dependent enzyme that functions as an important regulator of signa l-transduction processes in the brain. The naturally occurring cannabi noid Delta(9)-tetrahydrocannabinol (Delta(9)-THC) increased the activi ty of protein kinase C isolated from rat forebrain at concentrations o f 10 mu M and above. 11-OH-Delta(9)-THC, cannabinol and cannabidiol al so increased protein kinase C activity in the same concentration range , Delta(9)-THC (10 mu M) decreased the K-act of protein kinase C for c alcium from 28 mu M to 18 mu M and had no effect on the phosphatidylse rine concentration-stimulation relationship. At a concentration of 30 mu M, Delta(9)-THC increased the binding of [H-3]phorbol-12,13-dibutyr ate ([H-3]PDBu) to protein kinase C and decreased the K, for [H-3]PDBu from 8.2 nM to 5.4 nM. Delta(9)-THC also had effects on lipid orderin g of PS mice lies, producing a significant increase in the fluorescenc e anisotropy of 1,6-diphenyl-1,3,5-hexatriene at a concentration of 10 mu M. These data suggest that Delta(9)-THC activates protein kinase C via a novel mechanism, possibly as a result of effects on vesicle lip id physical characteristics.