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.
Castle
N A
NA
Anesthesia Research Laboratories, Harvard Medical School, Brigham and Women's Hospital, Boston, MA 02115.
D000818:Animals; D002024:Bufo marinus; D005576:Colforsin / Q000494:pharmacology*; D004553:Electric Conductivity; D007700:Kinetics; D008564:Membrane Potentials; D011188:Potassium / Q000378:metabolism*; D015221:Potassium Channels / Q000378:metabolism; D011901:Ranvier's Nodes / Q000187:drug effects / Q000378:metabolism*; D012964:Sodium / Q000378:metabolism*; D015222:Sodium Channels / Q000378:metabolism
D015221:Potassium Channels; D015222:Sodium Channels; D005576:Colforsin; D012964:Sodium; D011188:Potassium