BACE1 regulates voltage-gated sodium channels and neuronal activity

Doo Yeon Kim; Bryce W. Carey; Haibin Wang; Laura A.M. Ingano; Alexander M. Binshtok; Mary H. Wertz; Warren H. Pettingell; Ping He; Virginia M.Y. Lee; Clifford J. Woolf; Dora M. Kovacs

doi:10.1038/ncb1602

BACE1 regulates voltage-gated sodium channels and neuronal activity

Doo Yeon Kim, Bryce W. Carey, Haibin Wang, Laura A.M. Ingano, Alexander M. Binshtok, Mary H. Wertz, Warren H. Pettingell, Ping He, Virginia M.Y. Lee, Clifford J. Woolf, Dora M. Kovacs^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

264 Scopus citations

Abstract

BACE1 activity is significantly increased in the brains of Alzheimer's disease patients, potentially contributing to neurodegeneration. The voltage-gated sodium channel (Na_v1) β2-subunit (β2), a type I membrane protein that covalently binds to Na_v1 α-subunits, is a substrate for BACE1 and γ-secretase. Here, we find that BACE1γ-secretase cleavages release the intracellular domain of β2, which increases mRNA and protein levels of the pore-forming Na_v1.1 α-subunit in neuroblastoma cells. Similarly, endogenous β2 processing and Na_v1.1 protein levels are elevated in brains of BACE1-transgenic mice and Alzheimer's disease patients with high BACE1 levels. However, Na_v1.1 is retained inside the cells and cell surface expression of the Na_v1 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_v1 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.

Original language	English
Pages (from-to)	755-764
Number of pages	10
Journal	Nature Cell Biology
Volume	9
Issue number	7
DOIs	https://doi.org/10.1038/ncb1602
State	Published - Jul 2007
Externally published	Yes

Bibliographical note

Funding Information:
We thank S. Lichtenthaler (Ludwig-Maximilians-Universität, Germany) for the human Alzheimer’s disease ADAM10 construct, H. Federoff (University of Rochester) for the nectin-1 C-terminal antibody, A. Saunders (Drexel University) for the human BACE1 construct, J. Tang (University of Oklahoma) for the dr9 inhibitor, S. Tate (GlaxoSmithKline), and C. Plumpton (GlaxoSmithKline) for sodium channel antibodies. We would also like to thank L. Isom (University of Michigan) and R. E. Tanzi (Massachusetts General Hospital) for their helpful suggestions. This work is supported by grants from the National Institutes of Health, the National Institute of Aging and the John Douglas French Alzheimer’s Foundation.

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10.1038/ncb1602

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title = "BACE1 regulates voltage-gated sodium channels and neuronal activity",

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 BACE1γ-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.",

author = "Kim, {Doo Yeon} and Carey, {Bryce W.} and Haibin Wang and Ingano, {Laura A.M.} and Binshtok, {Alexander M.} and Wertz, {Mary H.} and Pettingell, {Warren H.} and Ping He and Lee, {Virginia M.Y.} and Woolf, {Clifford J.} and Kovacs, {Dora M.}",

note = "Funding Information: We thank S. Lichtenthaler (Ludwig-Maximilians-Universit{\"a}t, Germany) for the human Alzheimer{\textquoteright}s disease ADAM10 construct, H. Federoff (University of Rochester) for the nectin-1 C-terminal antibody, A. Saunders (Drexel University) for the human BACE1 construct, J. Tang (University of Oklahoma) for the dr9 inhibitor, S. Tate (GlaxoSmithKline), and C. Plumpton (GlaxoSmithKline) for sodium channel antibodies. We would also like to thank L. Isom (University of Michigan) and R. E. Tanzi (Massachusetts General Hospital) for their helpful suggestions. This work is supported by grants from the National Institutes of Health, the National Institute of Aging and the John Douglas French Alzheimer{\textquoteright}s Foundation.",

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AU - He, Ping

AU - Lee, Virginia M.Y.

AU - Woolf, Clifford J.

AU - Kovacs, Dora M.

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N2 - 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 BACE1γ-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.

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BACE1 regulates voltage-gated sodium channels and neuronal activity

Abstract

Bibliographical note

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