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T-Type Calcium Channels Are Inhibited by Fluoxetine and Its Metabolite Norfluoxetine

Département de Physiologie, Institut de Génomique Fonctionnelle, Centre National de la Recherche Scientifique Unité Mixte de Recherche 5203, Institut National de la Santé et de la Recherche Médicale U661, Universités de Montpellier I & II, Montpellier, France

Fluoxetine, a widely used antidepressant that primarily acts as a selective serotonin reuptake inhibitor, also inhibits various neuronal ion channels. Using the whole-cell patch-clamp technique, we have examined the effects of fluoxetine and norfluoxetine, its major active metabolite, on cloned low-voltage-activated T-type calcium channels (T channels) expressed in tsA 201 cells. Fluoxetine inhibited the three T channels Ca_V3.1, Ca_V3.2, and Ca_V3.3 in a concentration-dependent manner (IC₅₀ = 14, 16, and 30 µM, respectively). Norfluoxetine was a more potent inhibitor than fluoxetine, especially on the Ca_V3.3 T current (IC₅₀ = 5 µM). The fluoxetine block of T channels was voltage-dependent because it was significantly enhanced for T channels in the inactivated state. Fluoxetine caused a hyperpolarizing shift in steady-state inactivation, with a slower rate of recovery from the inactivated state. These results indicated a tighter binding of fluoxetine to the inactivated state than to the resting state of T channels, suggesting a more potent inhibition of T channels at physiological resting membrane potential. Indeed, fluoxetine and norfluoxetine at 1 µM strongly inhibited cloned T currents (50 and 75%, respectively) in action potential clamp experiments performed with firing activities of thalamocortical relay neurons. Altogether, these data demonstrate that clinically relevant concentrations of fluoxetine exert a voltage-dependent block of T channels that may contribute to this antidepressant's pharmacological effects.

Address correspondence to: Dr. Philippe Lory, Institut de Génomique Fonctionnelle, CNRS UMR 5203, INSERM U661, Universités de Montpellier I and II, 141 rue de la Cardonille, 34094 Montpellier cedex 05, France. E-mail: philippe.lory{at}igf.cnrs.fr

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