title: Fluoxetine blocks Nav1.5 channels via a mechanism similar to that of class 1 antiarrhythmics.
abstract: 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. Our study investigated the Nav1.5 blocking properties of fluoxetine, a selective serotonin reuptake 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 a similar IC50 [40 and 47 μM for the (+) and (-) isomers, 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 the S6 segment of domain (D) IV (DIVS6) significantly reduced the affinity of fluoxetine and its frequency-dependent inhibition. We used a noninactivating 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.
authors.affiliation: Centre de recherche, Institut universitaire en santé mentale de Québec, Quebec City, Quebec, Canada (H.P., O.T., J.-M.B., M.C.); State University of New York at Buffalo, Buffalo, New York (I.B.); Laboratoire de Pharmacologie Médicale, EA 4612 Neurocardiologie, Université Lyon 1, Lyon, France (Q.T.); Department of Psychiatry and Neuroscience, Université Laval, Quebec City, Quebec, Canada (J.-M.B.); Pôle Dapela, Département de l'autisme et des psychoses d'évolution lente de l'adulte, Centre Hospitalier Le Vinatier, Bron, France (D.F.); and Department of Medicine, Université Laval, Quebec City, Quebec, Canada (M.C.).
authors.forename: Hugo
authors.initials: H
authors.lastname: Poulin
authors.affiliation: Centre de recherche, Institut universitaire en santé mentale de Québec, Quebec City, Quebec, Canada (H.P., O.T., J.-M.B., M.C.); State University of New York at Buffalo, Buffalo, New York (I.B.); Laboratoire de Pharmacologie Médicale, EA 4612 Neurocardiologie, Université Lyon 1, Lyon, France (Q.T.); Department of Psychiatry and Neuroscience, Université Laval, Quebec City, Quebec, Canada (J.-M.B.); Pôle Dapela, Département de l'autisme et des psychoses d'évolution lente de l'adulte, Centre Hospitalier Le Vinatier, Bron, France (D.F.); and Department of Medicine, Université Laval, Quebec City, Quebec, Canada (M.C.).
authors.forename: Iva
authors.initials: I
authors.lastname: Bruhova
authors.affiliation: Centre de recherche, Institut universitaire en santé mentale de Québec, Quebec City, Quebec, Canada (H.P., O.T., J.-M.B., M.C.); State University of New York at Buffalo, Buffalo, New York (I.B.); Laboratoire de Pharmacologie Médicale, EA 4612 Neurocardiologie, Université Lyon 1, Lyon, France (Q.T.); Department of Psychiatry and Neuroscience, Université Laval, Quebec City, Quebec, Canada (J.-M.B.); Pôle Dapela, Département de l'autisme et des psychoses d'évolution lente de l'adulte, Centre Hospitalier Le Vinatier, Bron, France (D.F.); and Department of Medicine, Université Laval, Quebec City, Quebec, Canada (M.C.).
authors.forename: Quadiri
authors.initials: Q
authors.lastname: Timour
authors.affiliation: Centre de recherche, Institut universitaire en santé mentale de Québec, Quebec City, Quebec, Canada (H.P., O.T., J.-M.B., M.C.); State University of New York at Buffalo, Buffalo, New York (I.B.); Laboratoire de Pharmacologie Médicale, EA 4612 Neurocardiologie, Université Lyon 1, Lyon, France (Q.T.); Department of Psychiatry and Neuroscience, Université Laval, Quebec City, Quebec, Canada (J.-M.B.); Pôle Dapela, Département de l'autisme et des psychoses d'évolution lente de l'adulte, Centre Hospitalier Le Vinatier, Bron, France (D.F.); and Department of Medicine, Université Laval, Quebec City, Quebec, Canada (M.C.).
authors.forename: Olivier
authors.initials: O
authors.lastname: Theriault
authors.affiliation: Centre de recherche, Institut universitaire en santé mentale de Québec, Quebec City, Quebec, Canada (H.P., O.T., J.-M.B., M.C.); State University of New York at Buffalo, Buffalo, New York (I.B.); Laboratoire de Pharmacologie Médicale, EA 4612 Neurocardiologie, Université Lyon 1, Lyon, France (Q.T.); Department of Psychiatry and Neuroscience, Université Laval, Quebec City, Quebec, Canada (J.-M.B.); Pôle Dapela, Département de l'autisme et des psychoses d'évolution lente de l'adulte, Centre Hospitalier Le Vinatier, Bron, France (D.F.); and Department of Medicine, Université Laval, Quebec City, Quebec, Canada (M.C.).
authors.forename: Jean-Martin
authors.initials: JM
authors.lastname: Beaulieu
authors.affiliation: Centre de recherche, Institut universitaire en santé mentale de Québec, Quebec City, Quebec, Canada (H.P., O.T., J.-M.B., M.C.); State University of New York at Buffalo, Buffalo, New York (I.B.); Laboratoire de Pharmacologie Médicale, EA 4612 Neurocardiologie, Université Lyon 1, Lyon, France (Q.T.); Department of Psychiatry and Neuroscience, Université Laval, Quebec City, Quebec, Canada (J.-M.B.); Pôle Dapela, Département de l'autisme et des psychoses d'évolution lente de l'adulte, Centre Hospitalier Le Vinatier, Bron, France (D.F.); and Department of Medicine, Université Laval, Quebec City, Quebec, Canada (M.C.).
authors.forename: Dominique
authors.initials: D
authors.lastname: Frassati
authors.affiliation: Centre de recherche, Institut universitaire en santé mentale de Québec, Quebec City, Quebec, Canada (H.P., O.T., J.-M.B., M.C.); State University of New York at Buffalo, Buffalo, New York (I.B.); Laboratoire de Pharmacologie Médicale, EA 4612 Neurocardiologie, Université Lyon 1, Lyon, France (Q.T.); Department of Psychiatry and Neuroscience, Université Laval, Quebec City, Quebec, Canada (J.-M.B.); Pôle Dapela, Département de l'autisme et des psychoses d'évolution lente de l'adulte, Centre Hospitalier Le Vinatier, Bron, France (D.F.); and Department of Medicine, Université Laval, Quebec City, Quebec, Canada (M.C.) mohamed.chahine@phc.ulaval.ca.
authors.forename: Mohamed
authors.initials: M
authors.lastname: Chahine
mesh_terms: D000595:Amino Acid Sequence; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology; D001665:Binding Sites; D005473:Fluoxetine / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D057809:HEK293 Cells; D006801:Humans; D020128:Inhibitory Concentration 50; D015640:Ion Channel Gating; D008969:Molecular Sequence Data; D009154:Mutation; D062554:NAV1.5 Voltage-Gated Sodium Channel / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D017367:Selective Serotonin Reuptake Inhibitors / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D026941:Sodium Channel Blockers / Q000493:pharmacokinetics / Q000494:pharmacology*
chemical_list: D000889:Anti-Arrhythmia Agents; D005473:Fluoxetine; D062554:NAV1.5 Voltage-Gated Sodium Channel; D017367:Selective Serotonin Reuptake Inhibitors; D026941:Sodium Channel Blockers; C568320:SCN5A protein, human