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 (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.
authors.affiliation: Neurobiology of Disease Laboratory, Genetics and Aging Research Unit, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA.
authors.forename: Doo Yeon
authors.initials: DY
authors.lastname: Kim
authors.forename: Bryce W
authors.initials: BW
authors.lastname: Carey
authors.forename: Haibin
authors.initials: H
authors.lastname: Wang
authors.forename: Laura A M
authors.initials: LA
authors.lastname: Ingano
authors.forename: Alexander M
authors.initials: AM
authors.lastname: Binshtok
authors.forename: Mary H
authors.initials: MH
authors.lastname: Wertz
authors.forename: Warren H
authors.initials: WH
authors.lastname: Pettingell
authors.forename: Ping
authors.initials: P
authors.lastname: He
authors.forename: Virginia M-Y
authors.initials: VM
authors.lastname: Lee
authors.forename: Clifford J
authors.initials: CJ
authors.lastname: Woolf
authors.forename: Dora M
authors.initials: DM
authors.lastname: Kovacs
mesh_terms: 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*
chemical_list: 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