A carboxyl-terminal hydrophobic interface is critical to sodium channel function. Relevance to inherited disorders

J Biol Chem. 2006 Aug 18;281(33):24015-23. doi: 10.1074/jbc.M605473200. Epub 2006 Jun 22.


Perturbation of sodium channel inactivation, a finely tuned process that critically regulates the flow of sodium ions into excitable cells, is a common functional consequence of inherited mutations associated with epilepsy, skeletal muscle disease, autism, and cardiac arrhythmias. Understanding the structural basis of inactivation is key to understanding these disorders. Here we identify a novel role for a structural motif in the COOH terminus of the heart NaV1.5 sodium channel in determining channel inactivation. Structural modeling predicts an interhelical hydrophobic interface between paired EF hands in the proximal region of the NaV1.5 COOH terminus. The predicted interface is conserved among almost all EF hand-containing proteins and is the locus of a number of disease-associated mutations. Using the structural model as a guide, we provide biochemical and biophysical evidence that the structural integrity of this interface is necessary for proper Na+ channel inactivation gating. We thus demonstrate a novel role of the sodium channel COOH terminus structure in the control of channel inactivation and in pathologies caused by inherited mutations that disrupt it.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Acrylamide / chemistry
  • Amino Acid Sequence
  • Amino Acid Substitution / genetics
  • Arrhythmias, Cardiac / congenital
  • Arrhythmias, Cardiac / genetics*
  • Arrhythmias, Cardiac / metabolism
  • Cell Line
  • Computational Biology / methods
  • EF Hand Motifs
  • Humans
  • Hydrophobic and Hydrophilic Interactions
  • Ion Channel Gating / genetics
  • Molecular Sequence Data
  • Muscle Proteins / antagonists & inhibitors
  • Muscle Proteins / chemistry*
  • Muscle Proteins / genetics
  • Muscle Proteins / physiology*
  • NAV1.5 Voltage-Gated Sodium Channel
  • Peptide Fragments / antagonists & inhibitors
  • Peptide Fragments / chemistry*
  • Peptide Fragments / genetics
  • Peptide Fragments / physiology*
  • Protein Structure, Secondary
  • Protein Subunits / antagonists & inhibitors
  • Protein Subunits / chemistry
  • Protein Subunits / genetics
  • Protein Subunits / physiology
  • Sodium Channels / chemistry*
  • Sodium Channels / genetics
  • Sodium Channels / physiology*
  • Spectrometry, Fluorescence
  • Thermodynamics
  • Tryptophan / chemistry


  • Muscle Proteins
  • NAV1.5 Voltage-Gated Sodium Channel
  • Peptide Fragments
  • Protein Subunits
  • SCN5A protein, human
  • Sodium Channels
  • Acrylamide
  • Tryptophan