β-Secretase BACE1 regulates hippocampal and reconstituted M-currents in a β-subunit-like fashion

The β-secretase BACE1 is widely known for its pivotal role in the amyloidogenic pathway leading to Alzheimer's disease, but how its action on transmembrane proteins other than the amyloid precursor protein affects the nervous system is only beginning to be understood. We report here that BACE1...

Full description

Saved in:
Bibliographic Details
Published in:The Journal of neuroscience 2015-02, Vol.35 (8), p.3298-3311
Main Authors: Hessler, Sabine, Zheng, Fang, Hartmann, Stephanie, Rittger, Andrea, Lehnert, Sandra, Völkel, Meike, Nissen, Matthias, Edelmann, Elke, Saftig, Paul, Schwake, Michael, Huth, Tobias, Alzheimer, Christian
Format: Article
Language:English
Subjects:
Action Potentials
Amyloid Precursor Protein Secretases - genetics
Amyloid Precursor Protein Secretases - metabolism
Animals
Aspartic Acid Endopeptidases - genetics
Aspartic Acid Endopeptidases - metabolism
Cells, Cultured
Female
HEK293 Cells
Hippocampus - cytology
Hippocampus - metabolism
Hippocampus - physiology
Humans
KCNQ Potassium Channels - genetics
KCNQ Potassium Channels - metabolism
Male
Mice
Protein Binding
Protein Subunits - genetics
Protein Subunits - metabolism
Pyramidal Cells - metabolism
Pyramidal Cells - physiology
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:The β-secretase BACE1 is widely known for its pivotal role in the amyloidogenic pathway leading to Alzheimer's disease, but how its action on transmembrane proteins other than the amyloid precursor protein affects the nervous system is only beginning to be understood. We report here that BACE1 regulates neuronal excitability through an unorthodox, nonenzymatic interaction with members of the KCNQ (Kv7) family that give rise to the M-current, a noninactivating potassium current with slow kinetics. In hippocampal neurons from BACE1(-/-) mice, loss of M-current enhanced neuronal excitability. We relate the diminished M-current to the previously reported epileptic phenotype of BACE1-deficient mice. In HEK293T cells, BACE1 amplified reconstituted M-currents, altered their voltage dependence, accelerated activation, and slowed deactivation. Biochemical evidence strongly suggested that BACE1 physically associates with channel proteins in a β-subunit-like fashion. Our results establish BACE1 as a physiologically essential constituent of regular M-current function and elucidate a striking new feature of how BACE1 impacts on neuronal activity in the intact and diseased brain.
ISSN:0270-6474
1529-2401
DOI:10.1523/JNEUROSCI.3127-14.2015