Mechanisms and models of cardiac sodium channel inactivation

Kathryn E. Mangold, Brittany D. Brumback, Paweorn Angsutararux, Taylor L. Voelker, Wandi Zhu, Po Wei Kang, Jonathan D. Moreno, Jonathan R. Silva

Research output: Contribution to journalReview articlepeer-review

19 Scopus citations

Abstract

Shortly after cardiac Na+ channels activate and initiate the action potential, inactivation ensues within milliseconds, attenuating the peak Na+ current, INa, and allowing the cell membrane to repolarize. A very limited number of Na+ channels that do not inactivate carry a persistent INa, or late INa. While late INa is only a small fraction of peak magnitude, it significantly prolongs ventricular action potential duration, which predisposes patients to arrhythmia. Here, we review our current understanding of inactivation mechanisms, their regulation, and how they have been modeled computationally. Based on this body of work, we conclude that inactivation and its connection to late INa would be best modeled with a “feet-on-the-door” approach where multiple channel components participate in determining inactivation and late INa. This model reflects experimental findings showing that perturbation of many channel locations can destabilize inactivation and cause pathological late INa.

Original languageEnglish
Pages (from-to)517-533
Number of pages17
JournalChannels
Volume11
Issue number6
DOIs
StatePublished - Nov 2 2017

Keywords

  • computational models
  • inherited arrhythmias
  • late sodium current
  • sodium channels

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