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Structure of the Cardiac Sodium Channel.

Daohua Jiang1, Hui Shi2, Lige Tonggu1

  • 1Department of Pharmacology, University of Washington, Seattle, WA 98195, USA.

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|December 24, 2019
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Summary

We determined the structure of voltage-gated sodium channel NaV1.5, crucial for heartbeats. The structure reveals how the antiarrhythmic drug flecainide works and provides insights into channel gating and ion selectivity.

Keywords:
antiarrhytymic drugscryoelectron microscopy arrhythmiafast inactivationgating pore currentheartsodium channelsodium selectivity

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Area of Science:

  • Structural Biology
  • Cardiovascular Physiology
  • Molecular Pharmacology

Background:

  • Voltage-gated sodium channel NaV1.5 is essential for cardiac action potential generation and initiating the heartbeat.
  • Understanding NaV1.5 structure is key to comprehending cardiac electrophysiology and developing targeted therapies for arrhythmias.

Purpose of the Study:

  • To determine the high-resolution structures of NaV1.5.
  • To elucidate the structural basis for NaV1.5's unique properties, drug interactions, and gating mechanisms.
  • To provide insights into the molecular mechanisms underlying cardiac arrhythmias.

Main Methods:

  • X-ray crystallography to resolve NaV1.5 structures at 3.2-3.5 Å resolution.
  • Analysis of structural features, including unique glycosylation and subunit interaction sites.
  • Mapping of drug binding sites and functional implications of structural elements.

Main Results:

  • Reported NaV1.5 structures reveal unique glycosyl moiety and altered NaVβ subunit interactions.
  • The antiarrhythmic drug flecainide was found to specifically bind to the central pore cavity.
  • Structures show partially activated voltage sensors and a partially closed fast-inactivation gate, with insights into the IFM motif's role in inactivation.
  • The DEKA selectivity motif and charge-delocalization network governing Na+ ion transport were detailed.
  • Arrhythmia mutation sites exhibit significant conformational changes during gating.

Conclusions:

  • The determined structures offer unprecedented detail into NaV1.5's architecture, pharmacology, and gating dynamics.
  • Findings provide a structural basis for flecainide's antiarrhythmic action.
  • Insights into ion selectivity and the pathogenic mechanisms of NaV1.5 mutations in arrhythmias were gained.