The effects of 4-aminopyridine (4-AP), a specific blocker of outward K current, on voltage-activated transient outward K current 1(I) and inward Na current (I) were investigated on cultured rat cerebellar granule cells using the whole cell voltage-clamp K(A) Na 1technique. At the concentration of 1–5 mM, 4-AP inhibited both I and I. It reduced the amplitude of peak Na current without K(A) Na significant alteration of the steady-state activation and inactivation properties. The inhibitory effect was not enhanced by repeated 1depolarizing pulses (0.5 or 0.1 Hz), suggesting that the binding affinity of 4-AP on Na channels is state-independent. In contrast, the 1 effect of 4-AP on Na channels appeared to be voltage-dependent, the weaker inhibition occurred at more depolarization. Moreover, 4-AP 1 slowed both the activation and inactivation kinetics of Na current. These effects were similar to those induced by a-scorpion toxin and 1 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 11 1 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.