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First published on March 1, 2006; DOI: 10.1124/mol.105.020842

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Received for publication November 16, 2005.
Revised March 1, 2006.
Accepted for publication March 1, 2006.

T-type calcium channels are inhibited by fluoxetine and its metabolite norfluoxetine

Achraf Traboulsie 1, Jean Chemin 1, Elodie Kupfer 1, Joel Nargeot 1, Philippe Lory 1*

1 IGF - CNRS

* Address correspondence to: E-mail: philippe.lory{at}igh.cnrs.fr

Abstract

Fluoxetine (Prozac®), a widely used antidepressant that primary acts as a selective serotonin re-uptake 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, CaV3.1, CaV3.2 and CaV3.3, in a concentration-dependent manner (IC50 = 14, 16 and 30 µM respectively). Norfluoxetine was a more potent inhibitor than fluoxetine, especially on CaV3.3 T-current (IC50 = 5 µM). The fluoxetine block of T-channels was voltage-dependent since 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 thalamo-cortical 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.


Key words: Calcium (Votage-Gated Channels), Anti-depressants


This article has been cited by other articles:


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[Abstract] [Full Text] [PDF]


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