Non-proteolytic effect of beta-site APP-cleaving enzyme 1 (BACE1) on sodium channel function.
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.
Huth
Tobias
T
Institutes of Physiology, University of Kiel Olshausenstr. 40, 24098 Kiel, Germany.
Schmidt-Neuenfeldt
Karoline
K
Rittger
Andrea
A
Saftig
Paul
P
Reiss
Karina
K
Alzheimer
Christian
C
D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism*; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000378:metabolism*; D015153:Blotting, Western; D002460:Cell Line; D006801:Humans; D007150:Immunohistochemistry; D015640:Ion Channel Gating / Q000502:physiology; D008564:Membrane Potentials; D051379:Mice; D062551:NAV1.2 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015222:Sodium Channels / Q000378:metabolism*; D014162:Transfection; D062548:Voltage-Gated Sodium Channel beta-2 Subunit; D062585:Voltage-Gated Sodium Channel beta-4 Subunit
D062551:NAV1.2 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins; C568251:SCN2A protein, human; C117620:SCN2B protein, human; C477263:SCN4B protein, human; C000654500:Scn2a protein, mouse; D015222:Sodium Channels; D062548:Voltage-Gated Sodium Channel beta-2 Subunit; D062585:Voltage-Gated Sodium Channel beta-4 Subunit; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human