ArticleThe Journal of biological chemistry2016
The Human Ether-a-go-go-related Gene (hERG) Potassium Channel Represents an Unusual Target for Protease-mediated Damage.
Article in The Journal of biological chemistry, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 37 papers.
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Who cites it
37 citing papers in PubMed, 117 citations in OpenAlex.
- From Bacteria to Breakthroughs: Design and Evaluation of Gallocin-Based Peptide for Colorectal Cancer Therapeutic.Probiotics and antimicrobial proteins · 2026Article
- α-mannosidase I-dependent N-linked glycosylation affects hERG channel functional availability during reactivation.The journal of physiological sciences : JPS · 2026Article
- A Review of the Effects of Herbal Medicines on the Conductance of Ion Channels.Physiological research · 2026Review
- Amiodarone irrecoverably impairs the function of human ether-a-go-go-related gene potassium channels.Molecular pharmacology · 2026Article
- KCNH2-L693P Causes Long QT Syndrome Type 2 Through hERG Channel Dysfunction: Functional Validation of a Variant of Uncertain Significance.Molecular genetics & genomic medicine · 2025Article
- The identification of metabolites from gut microbiota in autism spectrum disorder via network pharmacology.Scientific reports · 2025Article
- GraphDeep-hERG: Graph Neural Network PharmacoAnalytics for Assessing hERG-Related Cardiotoxicity.Pharmaceutical research · 2025Article
- Evaluation of extra virgin olive oil compounds using computational methods: in vitro, ADMET, DFT, molecular docking and human gene network analysis study.BMC chemistry · 2025Article
- A natural small molecule isoginkgetin alleviates hypercholesterolemia and atherosclerosis by targeting ACLY.Theranostics · 2025Article
- Molecular docking, free energy calculations, ADMETox studies, DFT analysis, and dynamic simulations highlighting a chromene glycoside as a potential inhibitor of PknG inFrontiers in chemistry · 2025Article
- Microbial-based natural products as potential inhibitors targeting DNA gyrase B ofFrontiers in chemistry · 2025Article
- Non-clinical investigations about cytotoxic and anti-platelet activities of gamma-terpinene.Naunyn-Schmiedeberg's archives of pharmacology · 2024Article
- Fentanyl and Sudden Death-A Postmortem Perspective for Diagnosing and Predicting Risk.Diagnostics (Basel, Switzerland) · 2024Review
- Article
- Levels of Small Extracellular Vesicles Containing hERG-1 and Hsp47 as Potential Biomarkers for Cardiovascular Diseases.International journal of molecular sciences · 2024Article
- Molecular docking of antidiabetic molecules of libas (In silico pharmacology · 2024Article
- Gallocin-derived Engineered Peptides Targeting EGFR and VEGFR in Colorectal Cancer: A Bioinformatic Approach.Current topics in medicinal chemistry · 2024Article
- Computational identification of potential acetylcholinesterase (AChE) and monoamine oxidase-B inhibitors fromIn silico pharmacology · 2024Article
- Evaluating pro-arrhythmogenic effects of the T634S-hERG mutation: insights from a simulation study.Interface focus · 2023Article
- Revolutionizing Medicinal Chemistry: The Application of Artificial Intelligence (AI) in Early Drug Discovery.Pharmaceuticals (Basel, Switzerland) · 2023Review
Corrections and comments
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Authors and funding
5 authors at 1 institution in 1 country.
Funding
Abstract
The human ether-a-go-go-related gene (hERG) encodes the pore-forming subunit of the rapidly activating delayed rectifier potassium channel (IKr), which is important for cardiac repolarization. Dysfunction of hERG causes long QT syndrome and sudden death, which occur in patients with cardiac ischemia. Cardiac ischemia is also associated with activation, up-regulation, and secretion of various proteolytic enzymes. Here, using whole-cell patch clamp and Western blotting analysis, we demonstrate that the hERG/IKr channel was selectively cleaved by the serine protease, proteinase K (PK). Using molecular biology techniques including making a chimeric channel between protease-sensitive hERG and insensitive human ether-a-go-go (hEAG), as well as application of the scorpion toxin BeKm-1, we identified that the S5-pore linker of hERG is the target domain for proteinase K cleavage. To investigate the physiological relevance of the unique susceptibility of hERG to proteases, we show that cardiac ischemia in a rabbit model was associated with a reduction in mature ERG expression and an increase in the expression of several proteases, including calpain. Using cell biology approaches, we found that calpain-1 was actively released into the extracellular milieu and cleaved hERG at the S5-pore linker. Using protease cleavage-predicting software and site-directed mutagenesis, we identified that calpain-1 cleaves hERG at position Gly-603 in the S5-pore linker of hERG. Clarification of protease-mediated damage of hERG extends our understanding of hERG regulation. Damage of hERG mediated by proteases such as calpain may contribute to ischemia-associated QT prolongation and sudden cardiac death.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.