Protein kinase C (PKC) activity and its redistribution were determined in the frontal cortices of postmortem brains of bipolar affective disorder subjects and age-, sex-, and postmortem time-matched controls. Membrane and cytosolic PKC activity was determined by histone phosphorylation using [32P]-adenosine triphosphate as substrate. Specific PKC isozyme levels were assessed by Western blot analysis using antipeptide antibodies. Brain membrane-associated PKC activity was higher in bipolar vs. control tissue. An examination of the specific PKC isozymes in cortical homogenates revealed that cytosolic alpha- and membrane-associated gamma- and zeta PKC isozymes were elevated in cortices of bipolar affective disorder subjects, whereas cytosolic epsilon PKC was found to be reduced. In control brain slices, incubation with 1 mumol/L phorbol 12-myristate 13-acetate (PMA) caused an increase in membrane PKC activity, whereas cytosolic enzyme activity was decreased. This redistribution of the enzyme by PMA was markedly potentiated in brain slices of bipolar subjects. The results suggest that PKC-mediated phosphorylation is increased in brains of subjects with bipolar affective illness.