PERTURBATION OF SODIUM CHANNEL STRUCTURE BY AN INHERITED LONG QT SYNDROME MUTATION

The cardiac voltage-gated sodium channel (NaV1.5) underlies impulse conduction in the heart, and its depolarization-induced inactivation is essential in control of the duration of the QT interval of the electrocardiogram. Perturbation of NaV1.5 inactivation by drugs or inherited mutation can underlie and trigger cardiac arrhythmias. The carboxy terminus has an important role in channel inactivation, but complete structural information on its predicted structural domain is unknown. Here we measure interactions between the functionally critical distal carboxy terminus α-helix (H6) and the proximal structured EF-hand motif using transition-metal ion fluorescence resonance energy transfer. We measure distances at three loci along H6 relative to an intrinsic tryptophan, demonstrating the proximal–distal interaction in a contiguous carboxy terminus polypeptide. Using these data together with the existing NaV1.5 carboxy terminus nuclear magnetic resonance structure, we construct a model of the predicted structured region of the carboxy terminus. An arrhythmia-associated H6 mutant that impairs inactivation decreases fluorescence resonance energy transfer, indicating destabilization of the distal–proximal intramolecular interaction. These data provide a structural correlation to the pathological phenotype of the mutant channel. Perturbation of the cardiac voltage-gated sodium channel, NaV1.5, by drugs or inherited mutation can underlie and trigger cardiac arrhythmias. Here, the role of the NaV1.5 carboxy terminus in channel inactivation is investigated, and structural details of an arrhythmia associated H6 mutant are reported.

• Publication year

  2012

• Venue

  Nature Communications

• Publication date

  2012-01-01

• Fields of study

  Biology, Medicine, Chemistry

• Identifiers
  DOI 10.1038/ncomms1717PMID 22426227PMCID 3518026
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

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