title: BACE1 modulates gating of KCNQ1 (Kv7.1) and cardiac delayed rectifier KCNQ1/KCNE1 (IKs).
abstract: KCNQ1 (Kv7.1) proteins form a homotetrameric channel, which produces a voltage-dependent K(+) current. Co-assembly of KCNQ1 with the auxiliary β-subunit KCNE1 strongly up-regulates this current. In cardiac myocytes, KCNQ1/E1 complexes are thought to give rise to the delayed rectifier current IKs, which contributes to cardiac action potential repolarization. We report here that the type I membrane protein BACE1 (β-site APP-cleaving enzyme 1), which is best known for its detrimental role in Alzheimer's disease, but is also, as reported here, present in cardiac myocytes, serves as a novel interaction partner of KCNQ1. Using HEK293T cells as heterologous expression system to study the electrophysiological effects of BACE1 and KCNE1 on KCNQ1 in different combinations, our main findings were the following: (1) BACE1 slowed the inactivation of KCNQ1 current producing an increased initial response to depolarizing voltage steps. (2) Activation kinetics of KCNQ1/E1 currents were significantly slowed in the presence of co-expressed BACE1. (3) BACE1 impaired reconstituted cardiac IKs when cardiac action potentials were used as voltage commands, but interestingly augmented the IKs of ATP-deprived cells, suggesting that the effect of BACE1 depends on the metabolic state of the cell. (4) The electrophysiological effects of BACE1 on KCNQ1 reported here were independent of its enzymatic activity, as they were preserved when the proteolytically inactive variant BACE1 D289N was co-transfected in lieu of BACE1 or when BACE1-expressing cells were treated with the BACE1-inhibiting compound C3. (5) Co-immunoprecipitation and fluorescence recovery after photobleaching (FRAP) supported our hypothesis that BACE1 modifies the biophysical properties of IKs by physically interacting with KCNQ1 in a β-subunit-like fashion. Strongly underscoring the functional significance of this interaction, we detected BACE1 in human iPSC-derived cardiomyocytes and murine cardiac tissue and observed decreased IKs in atrial cardiomyocytes of BACE1-deficient mice.
authors.affiliation: Institut für Physiologie und Pathophysiologie, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, Germany.
authors.forename: Marianne
authors.initials: M
authors.lastname: Agsten
authors.affiliation: Institut für Physiologie und Pathophysiologie, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, Germany.
authors.forename: Sabine
authors.initials: S
authors.lastname: Hessler
authors.affiliation: Institut für Physiologie und Pathophysiologie, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, Germany.
authors.forename: Sandra
authors.initials: S
authors.lastname: Lehnert
authors.affiliation: Institut für Zelluläre und Molekulare Physiologie, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, Germany.
authors.forename: Tilmann
authors.initials: T
authors.lastname: Volk
authors.affiliation: Institute of Biochemistry, Christian-Albrechts-Universität, 24098 Kiel, Germany.
authors.forename: Andrea
authors.initials: A
authors.lastname: Rittger
authors.affiliation: Institut für Physiologie und Pathophysiologie, 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: Christian
authors.initials: C
authors.lastname: Raab
authors.affiliation: Genetics and Aging Research Unit, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA.
authors.forename: Doo Yeon
authors.initials: DY
authors.lastname: Kim
authors.affiliation: Department of Psychiatry and Psychotherapy, University Hospital, 91054 Erlangen, Germany.
authors.forename: Teja W
authors.initials: TW
authors.lastname: Groemer
authors.affiliation: Institute of Biochemistry, Christian-Albrechts-Universität, 24098 Kiel, Germany; Biochemie III, Fakultät für Chemie, Universität Bielefeld, 33501 Bielefeld, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Schwake
authors.affiliation: Institut für Physiologie und Pathophysiologie, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Alzheimer
authors.affiliation: Institut für Physiologie und Pathophysiologie, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, Germany. Electronic address: tobias.huth@fau.de.
authors.forename: Tobias
authors.initials: T
authors.lastname: Huth
mesh_terms: D000200:Action Potentials; D053829:Amyloid Precursor Protein Secretases / Q000172:deficiency* / Q000378:metabolism; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000172:deficiency* / Q000378:metabolism; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D047468:Immunoprecipitation; D015640:Ion Channel Gating; D051657:KCNQ1 Potassium Channel / Q000378:metabolism*; D007700:Kinetics; D008297:Male; D051379:Mice; D046912:Multiprotein Complexes / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000378:metabolism*; D010641:Phenotype; D024642:Potassium Channels, Voltage-Gated / Q000378:metabolism*; D011485:Protein Binding; D059748:Proteolysis
chemical_list: D051657:KCNQ1 Potassium Channel; C092068:Kcne1 protein, mouse; C496910:Kcnq1 protein, mouse; D046912:Multiprotein Complexes; D024642:Potassium Channels, Voltage-Gated; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509282:Bace1 protein, mouse
keywords: BACE1; Cardiomyocytes; I(Ks); KCNE1; KCNQ1; Kv7.1