BACE1 regulates voltage-gated sodium channels and neuronal activity

Nat Cell Biol. 2007 Jul;9(7):755-64. doi: 10.1038/ncb1602. Epub 2007 Jun 18.


BACE1 activity is significantly increased in the brains of Alzheimer's disease patients, potentially contributing to neurodegeneration. The voltage-gated sodium channel (Na(v)1) beta2-subunit (beta2), a type I membrane protein that covalently binds to Na(v)1 alpha-subunits, is a substrate for BACE1 and gamma-secretase. Here, we find that BACE1-gamma-secretase cleavages release the intracellular domain of beta2, which increases mRNA and protein levels of the pore-forming Na(v)1.1 alpha-subunit in neuroblastoma cells. Similarly, endogenous beta2 processing and Na(v)1.1 protein levels are elevated in brains of BACE1-transgenic mice and Alzheimer's disease patients with high BACE1 levels. However, Na(v)1.1 is retained inside the cells and cell surface expression of the Na(v)1 alpha-subunits and sodium current densities are markedly reduced in both neuroblastoma cells and adult hippocampal neurons from BACE1-transgenic mice. BACE1, by cleaving beta2, thus regulates Na(v)1 alpha-subunit levels and controls cell-surface sodium current densities. BACE1 inhibitors may normalize membrane excitability in Alzheimer's disease patients with elevated BACE1 activity.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / metabolism
  • Amyloid Precursor Protein Secretases / genetics
  • Amyloid Precursor Protein Secretases / physiology*
  • Animals
  • Aspartic Acid Endopeptidases / genetics
  • Aspartic Acid Endopeptidases / physiology*
  • Cell Line, Tumor
  • Cell Membrane / metabolism
  • Hippocampus / cytology
  • Humans
  • Ion Channel Gating
  • Mice
  • Mice, Transgenic
  • NAV1.1 Voltage-Gated Sodium Channel
  • Nerve Tissue Proteins / metabolism*
  • Neuroblastoma
  • Neurons / metabolism
  • Neurons / physiology*
  • Patch-Clamp Techniques
  • Protein Subunits / genetics
  • Protein Subunits / physiology
  • Rats
  • Sodium Channels / metabolism*


  • NAV1.1 Voltage-Gated Sodium Channel
  • Nerve Tissue Proteins
  • Protein Subunits
  • SCN1A protein, human
  • Scn1a protein, mouse
  • Scn1a protein, rat
  • Sodium Channels
  • Amyloid Precursor Protein Secretases
  • Aspartic Acid Endopeptidases
  • BACE1 protein, human
  • Bace1 protein, mouse