Abstract

Native myocardial voltage-gated sodium (NaV) channels function in macromolecular complexes comprising a pore-forming (α) subunit and multiple accessory proteins. Here, we investigated the impact of accessory NaVβ1 and NaVβ3 subunits on the functional effects of 2 well-known class Ib antiarrhythmics, lidocaine and ranolazine, on the predominant NaV channel α subunit, NaV1.5, expressed in the mammalian heart. We showed that both drugs stabilized the activated conformation of the voltage sensor of domain-III (DIII-VSD) in NaV1.5. In the presence of NaVβ1, the effect of lidocaine on the DIII-VSD was enhanced, whereas the effect of ranolazine was abolished. Mutating the main class Ib drug-binding site, F1760, affected but did not abolish the modulation of drug block by NaVβ1/β3. Recordings from adult mouse ventricular myocytes demonstrated that loss of Scn1b (NaVβ1) differentially affected the potencies of lidocaine and ranolazine. In vivo experiments revealed distinct ECG responses to i.p. injection of ranolazine or lidocaine in WT and Scn1b-null animals, suggesting that NaVβ1 modulated drug responses at the whole-heart level. In the human heart, we found that SCN1B transcript expression was 3 times higher in the atria than ventricles, differences that could, in combination with inherited or acquired cardiovascular disease, dramatically affect patient response to class Ib antiarrhythmic therapies.

Highlights

  • Inward Na+ currents (INa–) carried by voltage-gated (NaV) channels underlie the initiation and propagation of action potentials in the atria and ventricles [1]

  • Previous studies demonstrated that lidocaine shifts the activation of the DIII-voltage-sensing domains (VSDs) in rat NaV1.4 channels encoded by Scn4a and prominent in skeletal muscle in the hyperpolarizing direction [16, 29, 30]

  • Recent findings showed that a class Ib antiarrhythmic, mexiletine, which is similar in structure to lidocaine, affects the DIII-VSD conformation in NaV1.5 channels [18, 19]

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Summary

Introduction

Inward Na+ currents (INa–) carried by voltage-gated (NaV) channels underlie the initiation and propagation of action potentials in the atria and ventricles [1]. Functional NaV channels reflect the assembly of the 4 homologous domains (DI–DIV) in the pore-forming (α) subunit that are connected by intracellular linkers. Each domain contains 6 transmembrane segments (S1–S6). The VSDs undergo conformational changes upon membrane depolarization, which open the pore (S5–S6), enabling inward Na+ flux [2]. Native myocardial NaV channels function in macromolecular protein complexes, containing many regulatory and anchoring proteins that differentially affect channel function and localization based on the cell type [3]. There are 5 different types of NaVβ subunits, NaVβ1, NaVβ1B, NaVβ2, NaVβ3, and NaVβ4. NaVβ1, NaVβ1B, and NaVβ3 interact with the NaV α subunits noncovalently; NaVβ2 and NaVβ4 are linked covalently through the formation of disulfide bonds [4].

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