BACE1 regulates voltage-gated sodium channels and neuronal activity.
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.
Kim
Doo Yeon
DY
Neurobiology of Disease Laboratory, Genetics and Aging Research Unit, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA.
Carey
Bryce W
BW
Wang
Haibin
H
Ingano
Laura A M
LA
Binshtok
Alexander M
AM
Wertz
Mary H
MH
Pettingell
Warren H
WH
He
Ping
P
Lee
Virginia M-Y
VM
Woolf
Clifford J
CJ
Kovacs
Dora M
DM
D000544:Alzheimer Disease / Q000378:metabolism; D053829:Amyloid Precursor Protein Secretases / Q000235:genetics / Q000502:physiology*; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000235:genetics / Q000502:physiology*; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D006624:Hippocampus / Q000166:cytology; D006801:Humans; D015640:Ion Channel Gating; D051379:Mice; D008822:Mice, Transgenic; D062550:NAV1.1 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D009447:Neuroblastoma; D009474:Neurons / Q000378:metabolism / Q000502:physiology*; D018408:Patch-Clamp Techniques; D021122:Protein Subunits / Q000235:genetics / Q000502:physiology; D051381:Rats; D015222:Sodium Channels / Q000378:metabolism*
D062550:NAV1.1 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins; D021122:Protein Subunits; C568242:SCN1A protein, human; C568249:Scn1a protein, mouse; C568250:Scn1a protein, rat; D015222:Sodium Channels; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human; C509282:Bace1 protein, mouse