title: BACE1 and presenilin/γ-secretase regulate proteolytic processing of KCNE1 and 2, auxiliary subunits of voltage-gated potassium channels.
abstract: BACE1 and presenilin (PS)/γ-secretase play a major role in Alzheimer's disease pathogenesis by regulating amyloid-β peptide generation. We recently showed that these secretases also regulate the processing of voltage-gated sodium channel auxiliary β-subunits and thereby modulate membrane excitability. Here, we report that KCNE1 and KCNE2, auxiliary subunits of voltage-gated potassium channels, undergo sequential cleavage mediated by either α-secretase and PS/γ-secretase or BACE1 and PS/γ-secretase in cells. Elevated α-secretase or BACE1 activities increased C-terminal fragment (CTF) levels of KCNE1 and 2 in human embryonic kidney (HEK293T) and rat neuroblastoma (B104) cells. KCNE-CTFs were then further processed by PS/γ-secretase to KCNE intracellular domains. These KCNE cleavages were specifically blocked by chemical inhibitors of the secretases in the same cell models. We also verified our results in mouse cardiomyocytes and cultured primary neurons. Endogenous KCNE1- and KCNE2-CTF levels increased by 2- to 4-fold on PS/γ-secretase inhibition or BACE1 overexpression in these cells. Furthermore, the elevated BACE1 activity increased KCNE1 processing and shifted KCNE1/KCNQ1 channel activation curve to more positive potentials in HEK cells. KCNE1/KCNQ1 channel is a cardiac potassium channel complex, and the positive shift would lead to a decrease in membrane repolarization during cardiac action potential. Together, these results clearly showed that KCNE1 and KCNE2 cleavages are regulated by BACE1 and PS/γ-secretase activities under physiological conditions. Our results also suggest a functional role of KCNE cleavage in regulating voltage-gated potassium channels.
authors.affiliation: Neurobiology of Disease Laboratory, Genetics and Aging Research Unit, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA.
authors.forename: Carolyn C
authors.initials: CC
authors.lastname: Sachse
authors.forename: Young Hye
authors.initials: YH
authors.lastname: Kim
authors.forename: Marianne
authors.initials: M
authors.lastname: Agsten
authors.forename: Tobias
authors.initials: T
authors.lastname: Huth
authors.forename: Christian
authors.initials: C
authors.lastname: Alzheimer
authors.forename: Dora M
authors.initials: DM
authors.lastname: Kovacs
authors.forename: Doo Yeon
authors.initials: DY
authors.lastname: Kim
mesh_terms: D000595:Amino Acid Sequence; D053829:Amyloid Precursor Protein Secretases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D002478:Cells, Cultured; D057809:HEK293 Cells; D006801:Humans; D051657:KCNQ1 Potassium Channel / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D024642:Potassium Channels, Voltage-Gated / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D053763:Presenilins / Q000378:metabolism*; D059748:Proteolysis; D051381:Rats
chemical_list: C489622:KCNE1 protein, human; C489619:KCNE2 protein, human; C489621:KCNE2 protein, rat; D051657:KCNQ1 Potassium Channel; C496909:KCNQ1 protein, human; C092068:Kcne1 protein, mouse; C484268:Kcne1 protein, rat; C489620:Kcne2 protein, mouse; D024642:Potassium Channels, Voltage-Gated; D053763:Presenilins; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human; C509282:Bace1 protein, mouse; C509281:Bace1 protein, rat
keywords: Alzheimer's disease; KCNQ1; MiRP; MinK