Go to The Journal of Clinical Investigation
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Transfers
  • Advertising
  • Job board
  • Contact
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Immunology
    • Metabolism
    • Nephrology
    • Oncology
    • Pulmonology
    • All ...
  • Videos
  • Collections
    • Resource and Technical Advances
    • Clinical Medicine
    • Reviews
    • Editorials
    • Perspectives
    • Top read articles
  • JCI This Month
    • Current issue
    • Past issues

  • Current issue
  • Past issues
  • Specialties
  • In-Press Preview
  • Editorials
  • Viewpoint
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Transfers
  • Advertising
  • Job board
  • Contact
Modulation of the effects of class Ib antiarrhythmics on cardiac NaV1.5-encoded channels by accessory NaVβ subunits
Wandi Zhu, … , Jeanne M. Nerbonne, Jonathan R. Silva
Wandi Zhu, … , Jeanne M. Nerbonne, Jonathan R. Silva
Published June 22, 2021
Citation Information: JCI Insight. 2021;6(15):e143092. https://doi.org/10.1172/jci.insight.143092.
View: Text | PDF
Research Article Cardiology Therapeutics

Modulation of the effects of class Ib antiarrhythmics on cardiac NaV1.5-encoded channels by accessory NaVβ subunits

  • Text
  • PDF
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.

Authors

Wandi Zhu, Wei Wang, Paweorn Angsutararux, Rebecca L. Mellor, Lori L. Isom, Jeanne M. Nerbonne, Jonathan R. Silva

×

Figure 3

Altering the key local anesthetics’ binding site F1760 did not completely abolish NaVβ1/β3 modulations of ranolazine block.

Options: View larger image (or click on image) Download as PowerPoint
Altering the key local anesthetics’ binding site F1760 did not completel...
(A) Cryo-electron microscopy structure of human NaV1.4(11) (Protein Data Bank 6AGF) showing the relative locations of the F1760 residue, DIII, DIV, and NaVβ1. (B) Mutating the main local anesthetic binding residue F1760 to alanine (A) greatly reduced the hyperpolarizing shift in the DIII-VSD upon 10 mM lidocaine, as well as 4 mM ranolazine, observed in the WT channel (Figures 1 and 2). (C) Percentage of TB induced by 10 mM lidocaine and 4 mM ranolazine in the WT channel. The presence of NaVβ3 reduced lidocaine TB but enhanced ranolazine TB compared with the α-NaVβ1 complex. (D) Percentage of TB induced by 10 mM lidocaine and 4 mM ranolazine in the F1760A channel. In contrast to WT, NaVβ1 and NaVβ3 no longer exerted a significant effect on lidocaine and ranolazine TB. (E) UDB by lidocaine and ranolazine in F1760A channel coexpressed with NaVβ1 or NaVβ3. There was no change in lidocaine UDB comparing coexpression with NaVβ1 and NaVβ3. However, the presence of NaVβ1 caused a reduced ranolazine UDB compared with NaVβ3, a phenomenon that is similar to NaVβ1’s effects on the WT channel. Each data set represents mean ± SEM values from 3–6 cells. Unpaired 2-tailed Student’s t test was used to test significance (C–E). *P < 0.05.

Copyright © 2023 American Society for Clinical Investigation
ISSN 2379-3708

Sign up for email alerts