Open channel block of Kv3.1 currents by fluoxetine.
The action of fluoxetine, a serotonin reuptake inhibitor, on the cloned neuronal rat Kv3.1 channels stably expressed in Chinese hamster ovary cells was investigated using the whole-cell patch-clamp technique. Fluoxetine reduced Kv3.1 whole-cell currents in a reversible, concentration-dependent manner, with an IC(50) value and a Hill coefficient of 13.4 muM and 1.4, respectively. Fluoxetine accelerated the decay rate of inactivation of Kv3.1 currents without modifying the kinetics of current activation. The inhibition increased steeply between 0 and +30 mV, which corresponded with the voltage range for channel opening. In the voltage range positive to +30 mV, inhibition displayed a weak voltage dependence, consistent with an electrical distance delta of 0.38. The binding (k(+1)) and dissociation (k(-1)) rate constants for fluoxetine-induced block of Kv3.1 were 5.7 microM(-1)s(-1) and 53.5 s(-1), respectively. The theoretical K(D) value derived by k(-1)/k(+1) yielded 9.3 microM. Fluoxetine did not affect the ion selectivity of Kv3.1. Fluoxetine slowed the deactivation time course, resulting in a tail crossover phenomenon when the tail currents, recorded in the presence and absence of fluoxetine, were superimposed. Inhibition of Kv3.1 by fluoxetine was use-dependent. The present results suggest that fluoxetine acts on Kv3.1 currents as an open-channel blocker.
Sung
Min Ji
MJ
Department of Pharmacology, Institute for Medical Sciences, Chonbuk National University Medical School, Jeonju, Chonbuk, Republic of Korea.
Ahn
Hye Sook
HS
Hahn
Sang June
SJ
Choi
Bok Hee
BH
D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D004305:Dose-Response Relationship, Drug; D005473:Fluoxetine / Q000494:pharmacology*; D015640:Ion Channel Gating / Q000187:drug effects*; D008564:Membrane Potentials / Q000187:drug effects; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D018408:Patch-Clamp Techniques; D026902:Potassium Channel Blockers / Q000494:pharmacology*; D051381:Rats; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology*; D051670:Shaw Potassium Channels / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D013997:Time Factors; D014162:Transfection
D005473:Fluoxetine; D009419:Nerve Tissue Proteins; D026902:Potassium Channel Blockers; D017367:Selective Serotonin Reuptake Inhibitors; D051670:Shaw Potassium Channels; C098254:Kcnc1 protein, rat