An EF-hand in the sodium channel couples intracellular calcium to cardiac excitability

Tammy L. Wingo, Vikas N. Shah, Mark E. Anderson, Terry P. Lybrand, Walter J. Chazin, Jeffrey R. Balser

Research output: Contribution to journalArticlepeer-review

Abstract

Sodium channels initiate the electrical cascade responsible for cardiac rhythm, and certain life-threatening arrhythmias arise from Na+ channel dysfunction. We propose a novel mechanism for modulation of Na + channel function whereby calcium ions bind directly to the human cardiac Na+ channel (hH1) via an EF-hand motif in the C-terminal domain. A functional role for Ca2+ binding was identified electrophysiologically, by measuring Ca2+-induced modulation of hH1. A small hH1 fragment containing the EF-hand motif was shown to form a structured domain and to bind Ca2+ with affinity characteristic of calcium sensor proteins. Mutations in this domain reduce Ca2+ affinity in vitro and the inactivation gating effects of Ca2+ in electrophysiology experiments. These studies reveal the molecular basis for certain forms of long QT syndrome and other arrhythmia-producing syndromes, and suggest a potential pharmacological target for antiarrhythmic drug design.

Original languageEnglish (US)
Pages (from-to)219-225
Number of pages7
JournalNature Structural and Molecular Biology
Volume11
Issue number3
DOIs
StatePublished - Mar 1 2004
Externally publishedYes

ASJC Scopus subject areas

  • Structural Biology
  • Molecular Biology

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