The inhibitory effect of the melatonin receptor antagonist luzindole on voltage-activated transient outward K current (I) was K(A) investigated in cultured rat cerebellar granule cells using the whole cell voltage-clamp technique. At the concentration of 1 mM to 1 mM,luzindole reversibly inhibited I in a concentration-dependent manner. In addition to reducing the current amplitude of I,luzindole K(A) K(A) accelerated the fast inactivation of I channels and shifted the curves of voltage-dependent steady-state activation and inactivation of K(A) I by 16.6 mV and 27.0 mV, respectively. The inhibitory effect of luzindole was neither use-dependent nor voltage-dependent, K(A) suggesting that the binding affinity of luzindole to I channels is state-dependent. Including luzindole in the pipette solution, or K(A) extracellular application of 4 P-PDOT, an antagonist of melatonin receptors, did not change the luzindole-induced inhibitory effect on the I current, indicating that luzindole exerts its channel blocking inhibitory action at the extracellular mouth of the channel, and that the K(A)effect is not due to action of the melatonin receptors. Our data are the first demonstration that luzindole is able to block transient outward 1 K channels in rat cerebellar granule cells in a state-dependent manner, likely associated with extracellular interaction of the drug with the I inactivation gate.