期刊
NATURE STRUCTURAL & MOLECULAR BIOLOGY
卷 11, 期 3, 页码 219-225出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/nsmb737
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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 E-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.
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