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

The cannabinoids have been shown to affect both membrane lipid ordering and the activities of several membrane-associated proteins. We have investigated the effects of the cannabinoids on protein kinase C, a lipid-dependent enzyme that functions as an important regulator of signal-transduction processes in the brain. The naturally occurring cannabinoid Delta(9)-tetrahydrocannabinol (Delta(9)-THC) increased the activity of protein kinase C isolated from rat forebrain at concentrations of 10 mu M and above. 11-OH-Delta(9)-THC, cannabinol and cannabidiol also 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 calcium from 28 mu M to 18 mu M and had no effect on the phosphatidylserine concentration-stimulation relationship. At a concentration of 30 mu M, Delta(9)-THC increased the binding of [H-3]phorbol-12,13-dibutyrate ([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 ordering of PS mice lies, producing a significant increase in the fluorescence 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 lipid physical characteristics.