A DIRECT EFFECT OF FORSKOLIN ON SODIUM-CHANNEL BURSTING

A long-lasting component of current through voltage-dependent Na chann els is believed to contribute to the plateau phase of the cardiac acti on potential. Here we report that in cardiac ventricular myocytes fors kolin increases the contribution of a very slow component of decay (ta u=36 +/- 16 ms, n=13) in ensemble currents in response to step depolar izations 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 mu M). Rather, an increase in the probability of bursting behavior produced a forskolin concentr ation-dependent increase in the amplitude of this very slow component. This action of forskolin was not the result of stimulation of adenyly l cyclase because it was not affected when cAMP-dependent phosphorylat ion was inhibited by the protein kinase inhibitor H-89, and it could n ot 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-thiotri phosphate) (GTP [gamma S]) either applied to the bath or directly to t he intracellular face of the channel in inside-out macropatches. Furth ermore, 1,9-dideoxy-forskolin, which does not stimulate adenylyl cycla se and 6-(3-dimethylaminopropionyl)forskolin, a hydrophilic derivative of forskolin, also augmented late channel activity. Comparison of the characteristics of bursts in the presence of forskolin with those occ urring in its absence suggested that the increase in the frequency of long-lasting bursts produced by forskolin represents a direct interact ion of forskolin with the channel that augments, by up to tenfold, the probability that channels will have delayed inactivation.