The voltage-gated Na v 1.5 channel is essential for the propagation of action potentials in the heart. Malfunctions of this channel are known to cause hereditary diseases. It is a prime target for class 1 antiarrhythmic drugs and a number of antidepressants. Our study investigated the Na v 1.5 blocking properties of fluoxetine, a selective serotonin reuptake inhibitor. Na v 1.5 channels were expressed in HEK-293 cells, and Na 1 currents were recorded using the patch-clamp technique. Dose-response curves of racemic fluoxetine (IC 50 5 39 mM) and its optical isomers had a similar IC 50 [40 and 47 mM for the (1) and (2) isomers, respectively]. Norfluoxetine, a fluoxetine metabolite, had a higher affinity than fluoxetine, with an IC 50 of 29 mM. Fluoxetine inhibited currents in a frequency-dependent manner, shifted steady-state inactivation to more hyperpolarized potentials, and slowed the recovery of Na v 1.5 from inactivation. Mutating a phenylalanine (F1760) and a tyrosine (Y1767) in the S6 segment of domain (D) IV (DIVS6) significantly reduced the affinity of fluoxetine and its frequency-dependent inhibition. We used a noninactivating Na v 1.5 mutant to show that fluoxetine displays open-channel block behavior. The molecular model of fluoxetine in Na v 1.5 was in agreement with mutational experiments in which F1760 and Y1767 were found to be the key residues in binding fluoxetine. We concluded that fluoxetine blocks Na v 1.5 by binding to the class 1 antiarrhythmic site. The blocking of cardiac Na 1 channels should be taken into consideration when prescribing fluoxetine alone or in association with other drugs that may be cardiotoxic or for patients with conduction disorders.
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