PKC-independent inhibition of cardiac L-type Ca²⁺ channel current by phorbol esters

Active and inactive phorbol esters were applied to guinea pig ventricular myocytes to study the responses of L-type Ca²⁺ (I_Ca,L) and L-type Na⁺ (I_Na,L) currents. Phorbol 12-myristate 13-acetate (PMA) (10-100 nM) never stimulated I_Ca,L or I_Na,L and frequently depressed them by 5-30% in a voltage-independent manner. However, the phorbol ester consistently activated delayed-rectifying K₊ (I_K) and Cl^- currents. The inhibition of I_Ca,L occurred ∼3 times faster than comonitored stimulation of I_K, and I_ca,L and I_Na,L were unaffected by two interventions that suppressed I_K stimulation [pretreatment with 50 μM 1-(5-isoquinolinesulfonyl)-2-methylpiperazine (H-7) and dialysis with pCa 11 versus standard pCa 9 solution]. Inactive phorbol esters 4α-phorbol 12,13-didecanoate (α-PDD) and 4α-phorbol had little effect on I_K, but α-PDD had a PMA-like inhibitory effect on Ca²⁺ channel currents. We conclude that, unlike the stimulation of I_K by PMA, inhibition of Ca²⁺ channel current by phorbol esters is a protein kinase C-independent action.