Non-proteolytic effect of beta-site APP-cleaving enzyme 1 (BACE1) on sodium channel function.

Abstract	The beta-site APP-cleaving enzyme 1 (BACE1) is widely known for its pivotal role in the amyloidogenic pathway leading to Alzheimer's disease. Here, we elaborate on the recent finding that auxiliary subunits of voltage-gated sodium channels (beta2 and beta4) are BACE substrates. BACE1 produced complex effects on sodium channel gating that could be only partially explained by beta2/beta4 cleavage. To characterize the unexpected non-proteolytic effect of BACE1, we examined HEK cells co-transfected with only Nav1.2 and either normal or catalytically inactive BACE1. Both BACE1 variants produced virtually identical effects on sodium channel gating, which would lead to enhanced cellular excitability. The non-proteolytic BACE1 effect on Nav1.2 current was confirmed in murine neuroblastoma cells, which express sodium channels endogenously, but lack beta2 and beta4. Our study reveals an important facet of BACE1 function that should help to decipher the role of BACE1 in normal and demented brain.
Authors	Tobias Huth, Karoline Schmidt-Neuenfeldt, Andrea Rittger, Paul Saftig, Karina Reiss, Christian Alzheimer
Journal	Neurobiology of disease (Neurobiol Dis) Vol. 33 Issue 2 Pg. 282-9 (Feb 2009) ISSN: 1095-953X [Electronic] United States
PMID	19056495 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References	NAV1.2 Voltage-Gated Sodium Channel Nerve Tissue Proteins SCN2A protein, human SCN2B protein, human SCN4B protein, human Scn2a protein, mouse Sodium Channels Voltage-Gated Sodium Channel beta-2 Subunit Voltage-Gated Sodium Channel beta-4 Subunit Amyloid Precursor Protein Secretases Aspartic Acid Endopeptidases BACE1 protein, human
Topics	Amyloid Precursor Protein Secretases (metabolism) Animals Aspartic Acid Endopeptidases (metabolism) Blotting, Western Cell Line Humans Immunohistochemistry Ion Channel Gating (physiology) Membrane Potentials Mice NAV1.2 Voltage-Gated Sodium Channel Nerve Tissue Proteins (metabolism) Patch-Clamp Techniques Reverse Transcriptase Polymerase Chain Reaction Sodium Channels (metabolism) Transfection Voltage-Gated Sodium Channel beta-2 Subunit Voltage-Gated Sodium Channel beta-4 Subunit

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