ArticleProceedings of the National Academy of Sciences of the United States of America2016
Enhancement of hERG channel activity by scFv antibody fragments targeted to the PAS domain.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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Who cites it
18 citing papers in PubMed, 24 citations in OpenAlex.
- Sudden death-associated KCNH2 variants exert opposing effects on a nuclear subdomain of the cardiac potassium channel hERG1.The Journal of biological chemistry · 2026Article
- Sudden Death-AssociatedbioRxiv : the preprint server for biology · 2025Article
- A PAS-targeting hERG1 activator reduces arrhythmic events in Jervell and Lange-Nielsen syndrome patient-derived hiPSC-CMs.JCI insight · 2025Article
- Characterization of novel CD19-specific VHHs isolated from a camelid immune library by phage display.Journal of translational medicine · 2023Article
- hERG1 channel subunit composition mediates proton inhibition of rapid delayed rectifier potassium current (IThe Journal of biological chemistry · 2023Article
- Article
- Controlling ion channel function with renewable recombinant antibodies.The Journal of physiology · 2022Review
- Hysteretic hERG channel gating current recorded at physiological temperature.Scientific reports · 2022Article
- The ERG1 KFrontiers in molecular neuroscience · 2022Review
- Conformation-sensitive antibody reveals an altered cytosolic PAS/CNBh assembly during hERG channel gating.Proceedings of the National Academy of Sciences of the United States of America · 2021Article
- Therapeutic Antibodies Targeting Potassium Ion Channels.Handbook of experimental pharmacology · 2021Article
- Gating and regulation of KCNH (ERG, EAG, and ELK) channels by intracellular domains.Channels (Austin, Tex.) · 2020Review
- hERG Function in Light of Structure.Biophysical journal · 2020Review
- L51P, a novel mutation in the PAS domain of hERG channel, confers long QT syndrome by impairing channel activation.American journal of translational research · 2020Article
- Exploiting ion channel structure to assess rare variant pathogenicity.Heart rhythm · 2018Article
- Fluid flow modulates electrical activity in cardiac hERG potassium channels.The Journal of biological chemistry · 2018Article
- Localization and functional consequences of a direct interaction between TRIOBP-1 and hERG proteins in the heart.Journal of cell science · 2018Article
- Article
Corrections and comments
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Authors and funding
6 authors at 3 institutions in 2 countries.
Funding
Abstract
The human human ether-à-go-go-related gene (hERG) potassium channel plays a critical role in the repolarization of the cardiac action potential. Changes in hERG channel function underlie long QT syndrome (LQTS) and are associated with cardiac arrhythmias and sudden death. A striking feature of this channel and KCNH channels in general is the presence of an N-terminal Per-Arnt-Sim (PAS) domain. In other proteins, PAS domains bind ligands and modulate effector domains. However, the PAS domains of KCNH channels are orphan receptors. We have uncovered a family of positive modulators of hERG that specifically bind to the PAS domain. We generated two single-chain variable fragments (scFvs) that recognize different epitopes on the PAS domain. Both antibodies increase the rate of deactivation but have different effects on channel activation and inactivation. Importantly, we show that both antibodies, on binding to the PAS domain, increase the total amount of current that permeates the channel during a ventricular action potential and significantly reduce the action potential duration recorded in human cardiomyocytes. Overall, these molecules constitute a previously unidentified class of positive modulators and establish that allosteric modulation of hERG channel function through ligand binding to the PAS domain can be attained.
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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.