A calcium sensor in the sodium channel modulates cardiac excitability.
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.
Tan
Hanno L
HL
Department of Anesthesiology, Vanderbilt University School of Medicine, Nashville 37232, Tennessee, USA.
Kupershmidt
Sabina
S
Zhang
Rong
R
Stepanovic
Svetlana
S
Roden
Dan M
DM
Wilde
Arthur A M
AA
Anderson
Mark E
ME
Balser
Jeffrey R
JR
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
D002147:Calmodulin; D062554:NAV1.5 Voltage-Gated Sodium Channel; D011993:Recombinant Fusion Proteins; C568320:SCN5A protein, human; D015222:Sodium Channels; D002118:Calcium