4-aminopyridine, a specific blocker of K + channels, inhibited inward Na + current in rat cerebellar granule cells

Abstract

The effects of 4-aminopyridine (4-AP), a specific blocker of outward K + current, on voltage-activated transient outward K + current ( I K(A)) and inward Na + current ( I Na) were investigated on cultured rat cerebellar granule cells using the whole cell voltage-clamp technique. At the concentration of 1–5 mM, 4-AP inhibited both I K(A) and I Na. It reduced the amplitude of peak Na + current without significant alteration of the steady-state activation and inactivation properties. The inhibitory effect was not enhanced by repeated depolarizing pulses (0.5 or 0.1 Hz), suggesting that the binding affinity of 4-AP on Na + channels is state-independent. In contrast, the effect of 4-AP on Na + channels appeared to be voltage-dependent, the weaker inhibition occurred at more depolarization. Moreover, 4-AP slowed both the activation and inactivation kinetics of Na + current. These effects were similar to those induced by α-scorpion toxin and sea anemone toxins on Na + channels in other cell model. Our data demonstrate for the first time that 4-AP is able to block not only A-type K + channels, but also Na + channels in rat cerebellar granule cells. It is concluded that the inhibition exerted by 4-AP on Na + current likely differs from that provoked by local anesthetics. The possibility that the binding site of neurotoxin receptor 3 may be involved is discussed.