title: A calcium sensor in the sodium channel modulates cardiac excitability.
abstract: Sodium channels are principal molecular determinants responsible for myocardial conduction and maintenance of the cardiac rhythm. Calcium ions (Ca2+) have a fundamental role in the coupling of cardiac myocyte excitation and contraction, yet mechanisms whereby intracellular Ca2+ may directly modulate Na channel function have yet to be identified. Here we show that calmodulin (CaM), a ubiquitous Ca2+-sensing protein, binds to the carboxy-terminal 'IQ' domain of the human cardiac Na channel (hH1) in a Ca2+-dependent manner. This binding interaction significantly enhances slow inactivation-a channel-gating process linked to life-threatening idiopathic ventricular arrhythmias. Mutations targeted to the IQ domain disrupted CaM binding and eliminated Ca2+/CaM-dependent slow inactivation, whereas the gating effects of Ca2+/CaM were restored by intracellular application of a peptide modelled after the IQ domain. A naturally occurring mutation (A1924T) in the IQ domain altered hH1 function in a manner characteristic of the Brugada arrhythmia syndrome, but at the same time inhibited slow inactivation induced by Ca2+/CaM, yielding a clinically benign (arrhythmia free) phenotype.
authors.affiliation: Department of Anesthesiology, Vanderbilt University School of Medicine, Nashville 37232, Tennessee, USA.
authors.forename: Hanno L
authors.initials: HL
authors.lastname: Tan
authors.forename: Sabina
authors.initials: S
authors.lastname: Kupershmidt
authors.forename: Rong
authors.initials: R
authors.lastname: Zhang
authors.forename: Svetlana
authors.initials: S
authors.lastname: Stepanovic
authors.forename: Dan M
authors.initials: DM
authors.lastname: Roden
authors.forename: Arthur A M
authors.initials: AA
authors.lastname: Wilde
authors.forename: Mark E
authors.initials: ME
authors.lastname: Anderson
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Balser
mesh_terms: D000595:Amino Acid Sequence; D001145:Arrhythmias, Cardiac / Q000378:metabolism; D001665:Binding Sites; D002118:Calcium / Q000378:metabolism; D002147:Calmodulin / Q000378:metabolism*; D004594:Electrophysiology; D006801:Humans; D015640:Ion Channel Gating; D008969:Molecular Sequence Data; D009154:Mutation; D009206:Myocardium / Q000378:metabolism*; D062554:NAV1.5 Voltage-Gated Sodium Channel; D017434:Protein Structure, Tertiary; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D015222:Sodium Channels / Q000235:genetics / Q000378:metabolism*; D013577:Syndrome; D014693:Ventricular Fibrillation / Q000378:metabolism
chemical_list: D002147:Calmodulin; D062554:NAV1.5 Voltage-Gated Sodium Channel; D011993:Recombinant Fusion Proteins; C568320:SCN5A protein, human; D015222:Sodium Channels; D002118:Calcium