ArticleFASEB journal : official publication of the Federation of American Societies for Experimental Biology2013
BACE1 and presenilin/γ-secretase regulate proteolytic processing of KCNE1 and 2, auxiliary subunits of voltage-gated potassium channels.
Article in FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 36 papers, 1 of them a synthesis that pooled it.
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Who cites it
36 citing papers in PubMed, 1 synthesis or guideline pooled it.
- The causative role of amyloidosis in the cardiac complications of Alzheimer's disease: a comprehensive systematic review.The Journal of physiology · 2026Pooled it
- KCommunications medicine · 2026Article
- Hippocampus-targeted BDNF gene therapy to rescue cognitive impairments of Alzheimer's disease in multiple mouse models.Genes & diseases · 2026Article
- Article
- Suppression of MT5-MMP Reveals Early Modulation of Alzheimer's Pathogenic Events in Primary Neuronal Cultures of 5xFAD Mice.Biomolecules · 2024Article
- Secretase promotes AD progression: simultaneously cleave Notch and APP.Frontiers in aging neuroscience · 2024Review
- BACE1 in PV interneuron tunes hippocampal CA1 local circuits and resets priming of fear memory extinction.Molecular psychiatry · 2023Article
- Amyloid-β Effects on Peripheral Nerve: A New Model System.International journal of molecular sciences · 2023Article
- Gene, cell type, and drug prioritization analysis suggest genetic basis for the utility of diuretics in treating Alzheimer disease.HGG advances · 2023Article
- Review
- Therapeutic Potential of Targeting Regulated Intramembrane Proteolysis Mechanisms of Voltage-Gated Ion Channel Subunits and Cell Adhesion Molecules.Pharmacological reviews · 2022Review
- Biophysical KeLife · 2022Article
- Finding New Ways How to Control BACE1.The Journal of membrane biology · 2022Article
- The Potential of Gamma Secretase as a Therapeutic Target for Cardiac Diseases.Journal of personalized medicine · 2021Review
- Structural Studies Providing Insights into Production and Conformational Behavior of Amyloid-β Peptide Associated with Alzheimer's Disease Development.Molecules (Basel, Switzerland) · 2021Review
- Sodium channel β1 subunits participate in regulated intramembrane proteolysis-excitation coupling.JCI insight · 2021Article
- Advance genome editing technologies in the treatment of human diseases: CRISPR therapy (Review).International journal of molecular medicine · 2020Review
- RIP at the Synapse and the Role of Intracellular Domains in Neurons.Neuromolecular medicine · 2020Review
- β-Secretase BACE1 Is Required for Normal Cochlear Function.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2019Article
- Review
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7 authors.
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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.
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