title: β-Secretase BACE1 regulates hippocampal and reconstituted M-currents in a β-subunit-like fashion.
abstract: 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.
authors.affiliation: Institute of Physiology and Pathophysiology, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, Germany.
authors.forename: Sabine
authors.initials: S
authors.lastname: Hessler
authors.affiliation: Institute of Physiology and Pathophysiology, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, Germany.
authors.forename: Fang
authors.initials: F
authors.lastname: Zheng
authors.affiliation: Institute of Physiology and Pathophysiology, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, Germany.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Hartmann
authors.affiliation: Institute of Biochemistry, Christian-Albrechts-Universität, 24098 Kiel, Germany.
authors.forename: Andrea
authors.initials: A
authors.lastname: Rittger
authors.affiliation: Institute of Physiology and Pathophysiology, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, Germany.
authors.forename: Sandra
authors.identifier: http://orcid.org/0000-0002-5101-3181
authors.initials: S
authors.lastname: Lehnert
authors.affiliation: Institute of Physiology, Christian-Albrechts-Universität, 24098 Kiel, Germany.
authors.forename: Meike
authors.initials: M
authors.lastname: Völkel
authors.affiliation: Institute of Physiology and Pathophysiology, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, Germany.
authors.forename: Matthias
authors.identifier: http://orcid.org/0000-0001-5458-8127
authors.initials: M
authors.lastname: Nissen
authors.affiliation: Institute of Physiology, Christian-Albrechts-Universität, 24098 Kiel, Germany, Institute of Physiology, Otto-von-Guericke-Universität Magdeburg, 39120 Magdeburg, Germany, and.
authors.forename: Elke
authors.identifier: http://orcid.org/0000-0002-1976-1681
authors.initials: E
authors.lastname: Edelmann
authors.affiliation: Institute of Biochemistry, Christian-Albrechts-Universität, 24098 Kiel, Germany.
authors.forename: Paul
authors.initials: P
authors.lastname: Saftig
authors.affiliation: Institute of Biochemistry, Christian-Albrechts-Universität, 24098 Kiel, Germany, Biochemie III, Fakultät für Chemie, Universität Bielefeld, 33615 Bielefeld, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Schwake
authors.affiliation: Institute of Physiology and Pathophysiology, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, Germany, tobias.huth@fau.de christian.alzheimer@fau.de.
authors.forename: Tobias
authors.initials: T
authors.lastname: Huth
authors.affiliation: Institute of Physiology and Pathophysiology, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, Germany, tobias.huth@fau.de christian.alzheimer@fau.de.
authors.forename: Christian
authors.initials: C
authors.lastname: Alzheimer
mesh_terms: D000200:Action Potentials; D053829:Amyloid Precursor Protein Secretases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D005260:Female; D057809:HEK293 Cells; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism* / Q000502:physiology; D006801:Humans; D051656:KCNQ Potassium Channels / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D011485:Protein Binding; D021122:Protein Subunits / Q000235:genetics / Q000378:metabolism; D017966:Pyramidal Cells / Q000378:metabolism / Q000502:physiology
chemical_list: D051656:KCNQ Potassium Channels; D021122:Protein Subunits; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human
keywords: Alzheimer's disease; BACE1; KCNQ; M-current; epilepsy; hippocampus