Luzindole,a melatonin receptor antagonist,inhibits the transient outward K+ current in rat cerebellar granule cells

The inhibitory effect of the melatonin receptor antagonist luzindole on voltage-activated transient outward K⁺ current (I_K(A)) was investigated in cultured rat cerebellar granule cells using the whole cell voltage-clamp technique. At the concentration of 1 μM to 1 mM, luzindole reversibly inhibited I_K(A) in a concentration-dependent manner. In addition to reducing the current amplitude of I_K(A),luzindole accelerated the fast inactivation of I_K(A) channels and shifted the curves of voltage-dependent steady-state activation and inactivation of I_K(A) by +6.6 mV and −7.0 mV, respectively. The inhibitory effect of luzindole was neither use-dependent nor voltage-dependent, suggesting that the binding affinity of luzindole to I_K(A) channels is state-dependent. Including luzindole in the pipette solution, or extracellular application of 4 P-PDOT, an antagonist of melatonin receptors, did not change the luzindole-induced inhibitory effect on the I_K(A) current, indicating that luzindole exerts its channel blocking inhibitory action at the extracellular mouth of the channel, and that the effect is not due to action of the melatonin receptors. Our data are the first demonstration that luzindole is able to block transient outward K⁺ channels in rat cerebellar granule cells in a state-dependent manner, likely associated with extracellular interaction of the drug with the I_K(A) inactivation gate.