ArticleMolecular pharmacology2014
Fluoxetine blocks Nav1.5 channels via a mechanism similar to that of class 1 antiarrhythmics.
Article in Molecular pharmacology, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
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Who cites it
21 citing papers in PubMed, 30 citations in OpenAlex.
- Article
- Tetrodotoxin-resistant NaMolecular psychiatry · 2026Article
- A case report on the safety and efficacy of aripiprazole for depression in Brugada syndrome.The mental health clinician · 2025Article
- A structural atlas of druggable sites on NaChannels (Austin, Tex.) · 2024Review
- Inhibition of Ionic Currents by Fluoxetine in Vestibular Calyces in Different Epithelial Loci.International journal of molecular sciences · 2024Article
- TREK-1 and TREK-2 Knockout Mice Are Not Resistant to Halothane or Isoflurane.Anesthesiology · 2023Article
- Calculations of the binding free energies of the ComprehensiveBiophysics and physicobiology · 2023Article
- Structural modeling of NaBiophysics reports · 2021Article
- Block of Voltage-Gated Sodium Channels by Atomoxetine in a State- and Use-dependent Manner.Frontiers in pharmacology · 2021Article
- Something Old, Something New: Ion Channel Blockers as Potential Anti-Tuberculosis Agents.Frontiers in immunology · 2021Review
- Block of Voltage-Gated Sodium Channels as a Potential Novel Anti-cancer Mechanism of TIC10.Frontiers in pharmacology · 2021Article
- Predicting cardiac electrical response to sodium-channel blockade and Brugada syndrome using polygenic risk scores.European heart journal · 2019Article
- Fluoxetine Suppresses Glutamate- and GABA-Mediated Neurotransmission by Altering SNARE Complex.International journal of molecular sciences · 2019Article
- Carcinoid heart disease involving the left heart: a case report and biomarker analysis.ESC heart failure · 2019Article
- Role of TREK-1 in Health and Disease, Focus on the Central Nervous System.Frontiers in pharmacology · 2019Review
- hiPSC-CM Monolayer Maturation State Determines Drug Responsiveness in High Throughput Pro-Arrhythmia Screen.Scientific reports · 2017Article
- Modeling the human NaDrug design, development and therapy · 2017Article
- Inhibitory effects of neferine on Nav1.5 channels expressed in HEK293 cells.Journal of Huazhong University of Science and Technology. Medical sciences = Hua zhong ke ji da xue xue bao. Yi xue Ying De wen ban = Huazhong keji daxue xuebao. Yixue Yingdewen ban · 2016Article
- Voltage-gated sodium channel as a target for metastatic risk reduction with re-purposed drugs.F1000Research · 2015Review
- MTSET modification of D4S6 cysteines stabilize the fast inactivated state of Nav1.5 sodium channels.Frontiers in pharmacology · 2015Article
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Authors and funding
7 authors at 3 institutions in 3 countries.
Funding
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.
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