title: Ion channel regulation by β-secretase BACE1 - enzymatic and non-enzymatic effects beyond Alzheimer's disease.
abstract: β-site APP-cleaving enzyme 1 (BACE1) has become infamous for its pivotal role in the pathogenesis of Alzheimer's disease (AD). Consequently, BACE1 represents a prime target in drug development. Despite its detrimental involvement in AD, it should be quite obvious that BACE1 is not primarily present in the brain to drive mental decline. In fact, additional functions have been identified. In this review, we focus on the regulation of ion channels, specifically voltage-gated sodium and KCNQ potassium channels, by BACE1. These studies provide evidence for a highly unexpected feature in the functional repertoire of BACE1. Although capable of cleaving accessory channel subunits, BACE1 exerts many of its physiologically significant effects through direct, non-enzymatic interactions with main channel subunits. We discuss how the underlying mechanisms can be conceived and develop scenarios how the regulation of ion conductances by BACE1 might shape electric activity in the intact and diseased brain and heart.
authors.affiliation: a Institute of Physiology and Pathophysiology , Friedrich-Alexander-Universität Erlangen-Nürnberg , Erlangen , Germany.
authors.forename: Sandra
authors.initials: S
authors.lastname: Lehnert
authors.affiliation: a Institute of Physiology and Pathophysiology , Friedrich-Alexander-Universität Erlangen-Nürnberg , Erlangen , Germany.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Hartmann
authors.affiliation: b School of Psychology , University of Sussex , Brighton , UK.
authors.forename: Sabine
authors.initials: S
authors.lastname: Hessler
authors.affiliation: c Institute of Neuroscience, Technische Universität München , München , Germany.
authors.forename: Helmuth
authors.initials: H
authors.lastname: Adelsberger
authors.affiliation: a Institute of Physiology and Pathophysiology , Friedrich-Alexander-Universität Erlangen-Nürnberg , Erlangen , Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Huth
authors.affiliation: a Institute of Physiology and Pathophysiology , Friedrich-Alexander-Universität Erlangen-Nürnberg , Erlangen , Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Alzheimer
mesh_terms: D000544:Alzheimer Disease / Q000503:physiopathology; D053829:Amyloid Precursor Protein Secretases / Q000502:physiology*; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000502:physiology*; D006801:Humans; D015640:Ion Channel Gating; D009474:Neurons / Q000502:physiology; D024642:Potassium Channels, Voltage-Gated / Q000502:physiology; D061566:Voltage-Gated Sodium Channels / Q000502:physiology
chemical_list: D024642:Potassium Channels, Voltage-Gated; D061566:Voltage-Gated Sodium Channels; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human
keywords: BACE1; IKs; KCNQ channels; NaV channels; ataxia; direct interaction; epilepsy; hippocampus; resurgent current; β-subunit