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 microM 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.
Zhou
Mi-ou
MO
Center for Brain Science Research, Department of Physiology and Biophysics, School of Life Sciences, Fudan University, Shanghai 200433, China.
Jiao
Song
S
Liu
Zheng
Z
Zhang
Zhi-hong
ZH
Mei
Yan-ai
YA
D000818:Animals; D002478:Cells, Cultured; D002531:Cerebellum / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D026902:Potassium Channel Blockers / Q000494:pharmacology; D015221:Potassium Channels / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011956:Receptors, Cell Surface / Q000037:antagonists & inhibitors* / Q000502:physiology; D018160:Receptors, Cytoplasmic and Nuclear / Q000037:antagonists & inhibitors* / Q000502:physiology; D044094:Receptors, Melatonin; D014363:Tryptamines / Q000494:pharmacology*
D026902:Potassium Channel Blockers; D015221:Potassium Channels; D011956:Receptors, Cell Surface; D018160:Receptors, Cytoplasmic and Nuclear; D044094:Receptors, Melatonin; D014363:Tryptamines; C057154:luzindole