A direct effect of forskolin on sodium channel bursting.

A long-lasting component of current through voltage-dependent Na channels is believed to contribute to the plateau phase of the cardiac action potential. Here we report that in cardiac ventricular myocytes forskolin increases the contribution of a very slow component of decay (tau = 36 +/- 16 ms, n = 13) in ensemble currents in response to step depolarizations to 0 mV. Long-lasting bursts of openings (mean duration of 27 +/- 14 ms, n = 10) accounted for this behavior. The slow time constant of decay was not altered by forskolin (5-50 microM). Rather, an increase in the probability of bursting behavior produced a forskolin concentration-dependent increase in the amplitude of this very slow component. This action of forskolin was not the result of stimulation of adenylyl cyclase because it was not affected when cAMP-dependent phosphorylation was inhibited by the protein kinase inhibitor H-89, and it could not be mimicked by addition of isoproterenol, membrane-permeant cAMP [8-(4-chlorophenylthio)-cAMP], or the phosphatase inhibitor okadaic acid. In addition, bursting was not augmented by guanosine 5'-O-(3-thiotriphosphate) (GTP [gamma S]) either applied to the bath or directly to the intracellular face of the channel in inside-out macropatches. Furthermore, 1,9-dideoxy-forskolin, which does not stimulate adenylyl cyclase and 6-(3-dimethylaminopropionyl)-forskolin, a hydrophilic derivative of forskolin, also augmented late channel activity.(ABSTRACT TRUNCATED AT 250 WORDS)