title: Open channel block of Kv3.1 currents by fluoxetine.
abstract: 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.
authors.affiliation: Department of Pharmacology, Institute for Medical Sciences, Chonbuk National University Medical School, Jeonju, Chonbuk, Republic of Korea.
authors.forename: Min Ji
authors.initials: MJ
authors.lastname: Sung
authors.forename: Hye Sook
authors.initials: HS
authors.lastname: Ahn
authors.forename: Sang June
authors.initials: SJ
authors.lastname: Hahn
authors.forename: Bok Hee
authors.initials: BH
authors.lastname: Choi
mesh_terms: 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
chemical_list: D005473:Fluoxetine; D009419:Nerve Tissue Proteins; D026902:Potassium Channel Blockers; D017367:Selective Serotonin Reuptake Inhibitors; D051670:Shaw Potassium Channels; C098254:Kcnc1 protein, rat