T-type calcium channels are inhibited by fluoxetine and its metabolite norfluoxetine.
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(V)3.1, Ca(V)3.2, and Ca(V)3.3 in a concentration-dependent manner (IC(50) = 14, 16, and 30 microM, respectively). Norfluoxetine was a more potent inhibitor than fluoxetine, especially on the Ca(V)3.3 T current (IC(50) = 5 microM). 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 microM strongly inhibited cloned T currents (approximately 50 and approximately 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.
Traboulsie
Achraf
A
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.
Chemin
Jean
J
Kupfer
Elodie
E
Nargeot
Joël
J
Lory
Philippe
P
D002121:Calcium Channel Blockers / Q000494:pharmacology*; D020747:Calcium Channels, T-Type / Q000187:drug effects*; D002478:Cells, Cultured; D005473:Fluoxetine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D020128:Inhibitory Concentration 50; D026901:Membrane Transport Proteins / Q000187:drug effects; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors
C121855:CACNA1G protein, human; C479952:CACNA1H protein, human; C469757:CACNA1I protein, human; D002121:Calcium Channel Blockers; D020747:Calcium Channels, T-Type; D026901:Membrane Transport Proteins; D011994:Recombinant Proteins; D005473:Fluoxetine; C036139:norfluoxetine