Modulation of the cardiac sodium channel Nav1.5 by fibroblast growth factor homologous factor 1B

J Biol Chem. 2003 Jan 10;278(2):1029-36. doi: 10.1074/jbc.M207074200. Epub 2002 Oct 24.

Abstract

We have previously shown that fibroblast growth factor homologous factor 1B (FHF1B), a cytosolic member of the fibroblast growth factor family, associates with the sensory neuron-specific channel Na(v)1.9 but not with the other sodium channels present in adult rat dorsal root ganglia neurons. We show in this study that FHF1B binds to the C terminus of the cardiac voltage-gated sodium channel Na(v)1.5 and modulates the properties of the channel. The N-terminal 41 amino acid residues of FHF1B are essential for binding to Na(v)1.5, and the conserved acidic rich domain (amino acids 1773-1832) in the C terminus of Na(v)1.5 is sufficient for association with this factor. Binding of the growth factor to recombinant wild type human Na(v)1.5 in human embryonic kidney 293 cells produces a significant hyperpolarizing shift in the voltage dependence of channel inactivation. An aspartic acid to glycine substitution at position 1790 of the channel, which underlies one of the LQT-3 phenotypes of cardiac arrythmias, abolishes the interaction of the Na(v)1.5 channel with FHF1B. This is the first report showing that interaction with a growth factor can modulate properties of a voltage-gated sodium channel.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Amino Acid Sequence
  • Conserved Sequence
  • Fibroblast Growth Factors / physiology*
  • Humans
  • Long QT Syndrome / genetics
  • Molecular Sequence Data
  • Muscle Proteins / chemistry
  • Muscle Proteins / physiology*
  • Myocardium / metabolism*
  • NAV1.5 Voltage-Gated Sodium Channel
  • NAV1.9 Voltage-Gated Sodium Channel
  • Neuropeptides / physiology
  • Point Mutation
  • Sodium Channels / chemistry
  • Sodium Channels / physiology*
  • Transfection

Substances

  • FGF12 protein, human
  • Muscle Proteins
  • NAV1.5 Voltage-Gated Sodium Channel
  • NAV1.9 Voltage-Gated Sodium Channel
  • Neuropeptides
  • SCN11A protein, human
  • SCN5A protein, human
  • Scn11a protein, mouse
  • Scn5a protein, mouse
  • Scn5a protein, rat
  • Sodium Channels
  • Fibroblast Growth Factors