RT Journal Article
SR Electronic
T1 Fluoxetine Blocks Nav1.5 Channels Via a Mechanism Similar to That of Class 1 Antiarrhythmics
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP mol.114.093104
DO 10.1124/mol.114.093104
A1 Hugo Poulin
A1 Iva Bruhova
A1 Quadiri Timour
A1 Olivier Theriault
A1 Martin Beaulieu
A1 Dominique Frassati
A1 Mohamed Chahine
YR 2014
UL http://molpharm.aspetjournals.org/content/early/2014/07/15/mol.114.093104.abstract
AB The voltage-gated Nav1.5 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. The purpose of the present study was to investigate the Nav1.5 blocking properties of fluoxetine, a selective serotonin re-uptake inhibitor. Nav1.5 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 μM) and its optical isomers had similar IC50 (40 and 47 μM for the (+) and (-) isomer, respectively). Norfluoxetine, a fluoxetine metabolite, had a higher affinity than fluoxetine, with an IC50 of 29 μM. 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 DIVS6, significantly reduced the affinity of fluoxetine and its frequency-dependent inhibition. We used a non-inactivating Nav1.5 mutant to show that fluoxetine displays open-channel block behavior. The molecular model of fluoxetine in Nav1.5 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 Nav1.5 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.