Inhibition of Rat Brain Protein Kinase C by Lipid Soluble Psychotropics

Lipid soluble psychotropics inhibit brain PKC-catalyzed phosphorylation of exogenous and endogenous proteins to varying degrees. These drugs were better inhibitors of Ca²⁺/PL-dependent phosphorylation of histones (H) than that of Ca²⁺/PL-independent protamine sulfate (PrSO₄): antidepressants/antipsychotics displayed IC₅₀ of 0.1 to 0.16 mM towards H and 0.3 to 4.0 mM towards PrSO₄ phosphorylation. Sedatives/anesthetics were less efficient inhibitors with much higher IC₅₀ of 1.3 to 40 mM. Phosphorylation of a Ca²⁺-dependent but PL-independent p80 protein and of a cluster of Ca²⁺/PL-dependent proteins, p16-20, in brain was also inhibited by the antidepressants/antipsychotics but not by the sedatives/anesthetics. Phorbol ester binding studies revealed that these inhibitors do not compete for DAG binding site(s) on PKC. However, both drug-PL and drug-PKC interactions seem to be relevant in their mechanism of action. Furthermore, our data suggest that the hydrophobic nature of the propanamine side chain or its N-methylated version as well as the tricyclic nucleus influence drug-PKC interaction. Although many of these drugs have other accepted modes of action, modulation of PKC activity in brain, may be yet another aspect to be considered in their mechanism of action.