title: Mechanism of fluoxetine block of cloned voltage-activated potassium channel Kv1.3.
abstract: The effects of fluoxetine (Prozac), a widely used antidepressant drug, on Kv1.3 stably expressed in Chinese hamster ovary cells were examined using the whole-cell and excised inside-out configurations of the patch-clamp technique. In whole-cell recordings, fluoxetine accelerated the decay rate of inactivation of Kv1.3 and thus decreased the current amplitude at the end of the pulse in a concentration-dependent manner with an IC(50) value of 5.9 microM. The inhibition displayed a weak voltage dependence, increasing at more positive potentials. Neither the activation nor the steady-state inactivation curve was affected by fluoxetine. In addition, fluoxetine reduced the tail current amplitude and slowed the deactivation of the tail current, resulting in a crossover phenomenon. When applied to the internal side of the membrane in inside-out recordings, the inhibition by fluoxetine was much faster and more potent with an IC(50) value of 1.7 microM compared with whole-cell recordings. Norfluoxetine, the major metabolite of fluoxetine, also inhibited Kv1.3 in a concentration-dependent manner (IC(50) = 1.4 microM) in whole-cell recordings. To check whether the fluoxetine-induced inhibition demonstrated in cloned Kv1.3 could also be observed in native T lymphocytes, the effects of fluoxetine were investigated on human T lymphocytes. Fluoxetine also inhibited outward K(+) current in human T lymphocytes. Our results indicate that fluoxetine produced a concentration- and voltage-dependent inhibition of Kv1.3 that can be interpreted as an open channel block and that a binding site for fluoxetine is more accessible from the intracellular side.
authors.affiliation: Department of Physiology, College of Medicine, The Catholic University of Korea, Socho-gu, Seoul, Korea.
authors.forename: J S
authors.initials: JS
authors.lastname: Choi
authors.forename: S J
authors.initials: SJ
authors.lastname: Hahn
authors.forename: D J
authors.initials: DJ
authors.lastname: Rhie
authors.forename: S H
authors.initials: SH
authors.lastname: Yoon
authors.forename: Y H
authors.initials: YH
authors.lastname: Jo
authors.forename: M S
authors.initials: MS
authors.lastname: Kim
mesh_terms: D000818:Animals; D018687:Antidepressive Agents, Second-Generation / Q000378:metabolism / Q000494:pharmacology*; D016466:CHO Cells; D006224:Cricetinae; D004594:Electrophysiology; D005473:Fluoxetine / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D051664:Kv1.3 Potassium Channel; D011188:Potassium / Q000378:metabolism; D026902:Potassium Channel Blockers; D015221:Potassium Channels / Q000502:physiology; D024642:Potassium Channels, Voltage-Gated; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D013601:T-Lymphocytes / Q000187:drug effects* / Q000502:physiology
chemical_list: D018687:Antidepressive Agents, Second-Generation; C496973:KCNA3 protein, human; D051664:Kv1.3 Potassium Channel; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D011994:Recombinant Proteins; D005473:Fluoxetine; C036139:norfluoxetine; D011188:Potassium