ArticlePflugers Archiv : European journal of physiology2015
Kv1.5 blockers preferentially inhibit TASK-1 channels: TASK-1 as a target against atrial fibrillation and obstructive sleep apnea?
Article in Pflugers Archiv : European journal of physiology, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 29 papers.
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Who cites it
29 citing papers in PubMed, 67 citations in OpenAlex.
- One pocket to activate them all (?): Efforts on understanding the modulator pocket in K2P channels.Channels (Austin, Tex.) · 2026Review
- Structural determinants for GPCR-mediated inhibition of TASK K2P channels by diacylglycerol and its dysfunction in disease.The EMBO journal · 2026Article
- Rational design, synthesis, and evaluation of novel polypharmacological compounds targeting NaThe Journal of biological chemistry · 2025Article
- Potassium channel TASK-5 forms functional heterodimers with TASK-1 and TASK-3 to break its silence.Nature communications · 2024Article
- Ion occupancy of the selectivity filter controls opening of a cytoplasmic gate in the KNature communications · 2024Article
- Gain-of-function mutations in KCNK3 cause a developmental disorder with sleep apnea.Nature genetics · 2022Article
- Common Structural Pattern for Flecainide Binding in Atrial-Selective KPharmaceutics · 2022Article
- TWIK-Related Acid-Sensitive Potassium Channels (TASK-1) Emerge as Contributors to Tone Regulation in Renal Arteries at Alkaline pH.Frontiers in physiology · 2022Article
- Two-Pore-Domain Potassium (KCells · 2021Review
- Structural Insights into the Mechanisms and Pharmacology of KJournal of molecular biology · 2021Review
- Contribution of K2P Potassium Channels to Cardiac Physiology and Pathophysiology.International journal of molecular sciences · 2021Review
- Remodeling of Arterial Tone Regulation in Postnatal Development: Focus on Smooth Muscle Cell Potassium Channels.International journal of molecular sciences · 2021Review
- Article
- Current Drug Treatment Strategies for Atrial Fibrillation and TASK-1 Inhibition as an Emerging Novel Therapy Option.Frontiers in pharmacology · 2021Review
- Investigational Anti-Atrial Fibrillation Pharmacology and Mechanisms by Which Antiarrhythmics Terminate the Arrhythmia: Where Are We in 2020?Journal of cardiovascular pharmacology · 2020Review
- TASK-1 channel blockade by AVE1231 increases vasocontractile responses and BP in 1- to 2-week-old but not adult rats.British journal of pharmacology · 2020Article
- Article
- Pharmacologic TWIK-Related Acid-Sensitive K+ Channel (TASK-1) Potassium Channel Inhibitor A293 Facilitates Acute Cardioversion of Paroxysmal Atrial Fibrillation in a Porcine Large Animal Model.Journal of the American Heart Association · 2020Article
- Effects of the ventilatory stimulant, doxapram on human TASK-3 (KCNK9, K2P9.1) channels and TASK-1 (KCNK3, K2P3.1) channels.Acta physiologica (Oxford, England) · 2020Article
- The Experimental TASK-1 Potassium Channel Inhibitor A293 Can Be Employed for Rhythm Control of Persistent Atrial Fibrillation in a Translational Large Animal Model.Frontiers in physiology · 2020Article
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Authors and funding
8 authors at 3 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Atrial fibrillation and obstructive sleep apnea are responsible for significant morbidity and mortality in the industrialized world. There is a high medical need for novel drugs against both diseases, and here, Kv1.5 channels have emerged as promising drug targets. In humans, TASK-1 has an atrium-specific expression and TASK-1 is also abundantly expressed in the hypoglossal motor nucleus. We asked whether known Kv1.5 channel blockers, effective against atrial fibrillation and/or obstructive sleep apnea, modulate TASK-1 channels. Therefore, we tested Kv1.5 blockers with different chemical structures for their TASK-1 affinity, utilizing two-electrode voltage clamp (TEVC) recordings in Xenopus oocytes. Despite the low structural conservation of Kv1.5 and TASK-1 channels, we found all Kv1.5 blockers analyzed to be even more effective on TASK-1 than on Kv1.5. For instance, the half-maximal inhibitory concentration (IC50) values of AVE0118 and AVE1231 (A293) were 10- and 43-fold lower on TASK-1. Also for MSD-D, ICAGEN-4, S20951 (A1899), and S9947, the IC50 values were 1.4- to 70-fold lower than for Kv1.5. To describe this phenomenon on a molecular level, we used in silico models and identified unexpected structural similarities between the two drug binding sites. Kv1.5 blockers, like AVE0118 and AVE1231, which are promising drugs against atrial fibrillation or obstructive sleep apnea, are in fact potent TASK-1 blockers. Accordingly, block of TASK-1 channels by these compounds might contribute to the clinical effectiveness of these drugs. The higher affinity of these blockers for TASK-1 channels suggests that TASK-1 might be an unrecognized molecular target of Kv1.5 blockers effective in atrial fibrillation or obstructive sleep apnea.
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