Fluoxetine Blocks Nav1.5 Channels via a Mechanism Similar to That of Class 1 Antiarrhythmics

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+ currents were recorded using the patch-clamp technique. Dose-response curves of racemic fluoxetine (IC50 = 39 mu M) and its optical isomers had a similar IC50 [40 and 47 mu M for the (+) and (-) isomers, respectively]. Norfluoxetine, a fluoxetine metabolite, had a higher affinity than fluoxetine, with an IC50 of 29 mu M. Fluoxetine inhibited currents in a frequency-dependent manner, shifted steady-state inactivation to more hyperpolarized potentials, and slowed the recovery of Nav1.5 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+ 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.