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- Title
BACE1 regulates voltage-gated sodium channels and neuronal activity.
- Authors
Doo Yeon Kim; Carey, Bryce W.; Wang, Haibin; Ingano, Laura A. M.; Binshtok, Alexander M.; Wertz, Mary H.; Pettingell, Warren H.; Ping He; Lee, Virginia M.-Y.; Woolf, Clifford J.; Kovacs, Dora M.
- Abstract
BACE1 activity is significantly increased in the brains of Alzheimer's disease patients, potentially contributing to neurodegeneration. The voltage-gated sodium channel (Nav1) β2-subunit (β2), a type I membrane protein that covalently binds to Nav1 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 Nav1.1 α-subunit in neuroblastoma cells. Similarly, endogenous β2 processing and Nav1.1 protein levels are elevated in brains of BACE1-transgenic mice and Alzheimer's disease patients with high BACE1 levels. However, Nav1.1 is retained inside the cells and cell surface expression of the Nav1 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 Nav1 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.
- Publication
Nature Cell Biology, 2007, Vol 9, Issue 7, p755
- ISSN
1465-7392
- Publication type
Academic Journal
- DOI
10.1038/ncb1602