INHIBITION OF THE SPONTANEOUS RATE OF CONTRACTION OF NEONATAL CARDIACMYOCYTES BY PROTEIN-KINASE-C ISOZYMES - A PUTATIVE ROLE FOR THE EPSILON-ISOZYME

Protein kinase C (PKC) enzymes regulate numerous cardiac functions. In the present study, we determined the effects of the PKC-activating dr ug 4-beta phorbol 12-myristate 13-acetate (4-beta PMA) on the rate of contraction and correlated these changes with the distribution and lev els of alpha-, beta-, delta-, epsilon-, and zeta-PKC isozymes by using neonatal rat cardiac myocytes in culture. Treatment with 0.3 to 100 n mol/L 4-beta PMA caused negative chronotropic effects bn contraction. This effect was maximal at a concentration of 3 nmol/L 4-beta PMA and correlated with redistribution of the alpha- and epsilon-PKC isozymes from the cytosolic to the particulate cell fraction. After a 1-hour tr eatment with 100 nmol/L PMA, the alpha- and beta-PKC isozymes and an 8 0-kD zeta-like PKC isozyme were greatly diminished (downregulated), ye t the negative chronotropic effect was sustained. Therefore, our resul ts are most consistent with a role for the epsilon-PKC isozyme in supp ressing the contraction rate of neonatal rat cardiac myocytes. Underst anding the role(s) of individual PKC isozymes in the modulation of car diac functions may ultimately yield more selective targets for therapi es of cardiac disorders.