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BACE1 regulates voltage-gated sodium channels and neuronal activity
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Journal Article
BACE1 regulates voltage-gated sodium channels and neuronal activity
2007
Overview
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) β2-subunit (β2), a type I membrane protein that covalently binds to Na
v
1 α-subunits, is a substrate for BACE1 and γ-secretase. Here, we find that BACE1–γ-secretase cleavages release the intracellular domain of β2, which increases mRNA and protein levels of the pore-forming Na
v
1.1 α-subunit in neuroblastoma cells. Similarly, endogenous β2 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 α-subunits and sodium current densities are markedly reduced in both neuroblastoma cells and adult hippocampal neurons from
BACE1
-transgenic mice. BACE1, by cleaving β2, thus regulates Na
v
1 α-subunit levels and controls cell-surface sodium current densities. BACE1 inhibitors may normalize membrane excitability in Alzheimer's disease patients with elevated BACE1 activity.
Publisher
Nature Publishing Group UK,Nature Publishing Group
Subject
Alzheimer Disease - metabolism
/ Amyloid Precursor Protein Secretases - genetics
/ Amyloid Precursor Protein Secretases - physiology
/ Animals
/ Aspartic Acid Endopeptidases - genetics
/ Aspartic Acid Endopeptidases - physiology
/ Biomedical and Life Sciences
/ Humans
/ Mice
/ NAV1.1 Voltage-Gated Sodium Channel
/ Nerve Tissue Proteins - metabolism
/ Protein Subunits - physiology
/ Proteins
/ Rats
/ Sodium
