An EF-hand in the sodium channel couples intracellular calcium to cardiac excitability.
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 Ca(2+) binding was identified electrophysiologically, by measuring Ca(2+)-induced modulation of hH1. A small hH1 fragment containing the EF-hand motif was shown to form a structured domain and to bind Ca(2+) with affinity characteristic of calcium sensor proteins. Mutations in this domain reduce Ca(2+) affinity in vitro and the inactivation gating effects of Ca(2+) 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.
Wingo
Tammy L
TL
Department of Pharmacology, Vanderbilt University, Nashville, Tennessee 37232, USA.
Shah
Vikas N
VN
Anderson
Mark E
ME
Lybrand
Terry P
TP
Chazin
Walter J
WJ
Balser
Jeffrey R
JR
D000595:Amino Acid Sequence; D001665:Binding Sites; D002118:Calcium / Q000494:pharmacology*; D002147:Calmodulin; D020832:EF Hand Motifs / Q000235:genetics / Q000502:physiology*; D004594:Electrophysiology; D006321:Heart / Q000502:physiology*; D006801:Humans; D008954:Models, Biological; D009154:Mutation; D015222:Sodium Channels / Q000737:chemistry / Q000187:drug effects / Q000502:physiology*; D013057:Spectrum Analysis
D002147:Calmodulin; D015222:Sodium Channels; D002118:Calcium