Lidocaine block of human heart sodium channels expressed in Xenopus oocytes

Chahine, Mohamed; Chen, L Q; Barchi, Robert L.; Kallen, Roland G.; Horn, Richard

doi:10.1016/0022-2828(92)93090-7

Cited by 45 publications

(30 citation statements)

References 17 publications

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“…Use-dependence occurs because drug-modified channels slowly recover only at hyperpolarized voltages. Class 1 antiarrhythmic drugs and local anesthetics have a similar effect (Chahine et al, 1992). We thus determined whether fluoxetine could inhibit Na 1 currents by mutating residues in the class 1 antiarrhythmic drug binding site.…”

Section: Discussionmentioning

confidence: 99%

Fluoxetine Blocks Na_v1.5 Channels via a Mechanism Similar to That of Class 1 Antiarrhythmics

et al. 2014

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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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Section: Discussionmentioning

confidence: 99%

Fluoxetine Blocks Na_v1.5 Channels via a Mechanism Similar to That of Class 1 Antiarrhythmics

et al. 2014

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“…Our homology modeling of the inner-pore region did not face the problems we encountered when we modeled the outer pore. Local anesthetics are well studied inner-pore blockers of sodium channels (e.g., Chahine et al, 1992 Fig. 3.…”

Section: Sodium Channel Block By Tetrodotoxin and Local Anesthetics 99mentioning

confidence: 99%

Architecture and Pore Block of Eukaryotic Voltage-Gated Sodium Channels in View of NavAb Bacterial Sodium Channel Structure

Tikhonov

Zhorov²

2012

Mol Pharmacol

111

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The X-ray structure of the bacterial sodium channel NavAb provides a new template for the study of sodium and calcium channels. Unlike potassium channels, NavAb contains P2 helices in the outer-pore region. Because the sequence similarity between eukaryotic and prokaryotic sodium channels in this region is poor, the structural similarity is unclear. We analyzed it by using experimental data on tetrodotoxin block of sodium channels. Key tetrodotoxin-binding residues are outer carboxylates in repeats I, II, and IV, three positions downstream from the selectivity-filter residues. In a NavAb-based model of Nav1 channels derived from the sequence alignment without insertions/deletions, the outer carboxylates did not face the pore and therefore did not interact with tetrodotoxin. The hypothesis that the evolutionary appearance of Nav1 channels involved point deletions in an ancestral channel between the selectivity filter and the outer carboxylates allowed building of a NavAbbased model with tetrodotoxin-channel contacts similar to those proposed previously. This hypothesis also allowed us to reproduce in Nav1 the folding-stabilizing contacts between long-side chain residues in P1 and P2, which are seen in NavAb. The NavAb-based inner-pore model of Nav1 preserved major features of our previous KcsA-based models, including the access pathway for ligands through the repeat III/IV interface and their interactions with specific residues. Thus, structural properties of eukaryotic voltage-gated sodium channels that are suggested by functional data were reproduced in the NavAbbased models built by using the unaltered template structure but with adjusted sequence alignment. Sequences of eukaryotic calcium channels aligned with NavAb without insertions/ deletions, which suggests that NavAb is a promising basis for the modeling of calcium channels.

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“…Many class I antiarrhythmic drugs act by preferentially binding to inactivated states of Na ϩ channels, resulting in a hyperpolarizing shift in steady-state availability (8). To test this potential mechanism, the effects of ranolazine on the activation and steady-state inactivation of the channels was examined (Supplemental Material, Supplemental Fig.…”

Section: Phenotypic Characterization and Clinical Findings Of A Uniqumentioning

confidence: 99%

Y1767C, a novel SCN5A mutation, induces a persistent Na⁺ current and potentiates ranolazine inhibition of Na_v1.5 channels

Huang

Priori

Napolitano

et al. 2011

American Journal of Physiology-Heart and Circulatory Physiology

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Long QT syndrome type 3 (LQT3) has been traced to mutations of the cardiac Na+ channel (Nav1.5) that produce persistent Na+ currents leading to delayed ventricular repolarization and torsades de pointes. We performed mutational analyses of patients suffering from LQTS and characterized the biophysical properties of the mutations that we uncovered. One LQT3 patient carried a mutation in the SCN5A gene in which the cysteine was substituted for a highly conserved tyrosine (Y1767C) located near the cytoplasmic entrance of the Nav1.5 channel pore. The wild-type and mutant channels were transiently expressed in tsA201 cells, and Na+ currents were recorded using the patch-clamp technique. The Y1767C channel produced a persistent Na+ current, more rapid inactivation, faster recovery from inactivation, and an increased window current. The persistent Na+ current of the Y1767C channel was blocked by ranolazine but not by many class I antiarrhythmic drugs. The incomplete inactivation, along with the persistent activation of Na+ channels caused by an overlap of voltage-dependent activation and inactivation, known as window currents, appeared to contribute to the LQTS phenotype in this patient. The blocking effect of ranolazine on the persistent Na+ current suggested that ranolazine may be an effective therapeutic treatment for patients with this mutation. Our data also revealed the unique role for the Y1767 residue in inactivating and forming the intracellular pore of the Nav1.5 channel.

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Lidocaine block of human heart sodium channels expressed in Xenopus oocytes

Cited by 45 publications

References 17 publications

Fluoxetine Blocks Na_v1.5 Channels via a Mechanism Similar to That of Class 1 Antiarrhythmics

Fluoxetine Blocks Na_v1.5 Channels via a Mechanism Similar to That of Class 1 Antiarrhythmics

Architecture and Pore Block of Eukaryotic Voltage-Gated Sodium Channels in View of NavAb Bacterial Sodium Channel Structure

Y1767C, a novel SCN5A mutation, induces a persistent Na⁺ current and potentiates ranolazine inhibition of Na_v1.5 channels

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Lidocaine block of human heart sodium channels expressed in Xenopus oocytes

Cited by 45 publications

References 17 publications

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

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

Architecture and Pore Block of Eukaryotic Voltage-Gated Sodium Channels in View of NavAb Bacterial Sodium Channel Structure

Y1767C, a novel SCN5A mutation, induces a persistent Na+ current and potentiates ranolazine inhibition of Nav1.5 channels

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Fluoxetine Blocks Na_v1.5 Channels via a Mechanism Similar to That of Class 1 Antiarrhythmics

Fluoxetine Blocks Na_v1.5 Channels via a Mechanism Similar to That of Class 1 Antiarrhythmics

Y1767C, a novel SCN5A mutation, induces a persistent Na⁺ current and potentiates ranolazine inhibition of Na_v1.5 channels