Inhibition of voltage-dependent Na+ and K+ currents by forskolin in nodes of Ranvier.

The effect of forskolin on voltage-activated Na+ and K+ currents in nodes of Ranvier from the toad, Bufo marinus, has been examined using the vaseline-gap voltage-clamp technique. Peak Na+ currents (INa) were reduced by 35% and the rate of decline of Na+ current during continuous depolarization was accelerated following treatment with 450 microM forskolin. However, the voltage-dependence of steady-state inactivation as well as the rate of recovery from fast inactivation remained unchanged. Upon repetitive depolarization at 1-10 Hz, a further inhibition of INa (approximately 60%) was observed. This use-dependent or phasic inhibition recovers slowly at -80 mV (tau approximately 13 s) and had a voltage-dependence like that of activation of the Na conductance. Near maximal steady-state phasic inhibition occurred with depolarizing pulse durations of only 4 ms, consistent with a direct involvement of the open Na+ channel in the blocking process. Inhibition of the delayed K+ current (IK) was characterized by a concentration-dependent reduction in steady-state current amplitude (IC50 approximately 80 microM) and a concentration-independent acceleration of current inactivation. A similar inhibition of IK was obtained with 1,9-dideoxyforskolin, a homolog which does not activate adenylate cyclase (AC). The results suggest that the inhibition IK and perhaps INa follows directly from drug binding and is not a consequence of AC activation.