Identification of the A293 (AVE1231) Binding Site in the Cardiac Two-Pore-Domain Potassium Channel TASK-1: a Common Low Affinity Antiarrhythmic Drug Binding Site
| Autor: | Wolfgang Wenzel, Antonius Ratte, Maximilian Waibel, Niels Decher, Aytug K. Kiper, Hugo A. Katus, Priya Anad, Constanze Schmidt, Manuel Kraft, Wendy González, Susanne Rinné, Felix Wiedmann, Mauricio Bedoya |
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| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Technology Atrial action potential Physiology A293 A1899 Mutation Missense Nerve Tissue Proteins Propafenone Pharmacology Amiodarone lcsh:Physiology K2P3.1 lcsh:Biochemistry 03 medical and health sciences Xenopus laevis 0302 clinical medicine Potassium Channels Tandem Pore Domain medicine Animals Humans lcsh:QD415-436 Binding site TASK-1 Atrial cardiomyopathy chemistry.chemical_classification Binding Sites lcsh:QP1-981 Mutagenesis Atrial fibrillation AVE1231 Potassium channel Two-pore-domain potassium channels Amino acid 030104 developmental biology chemistry Amino Acid Substitution Atrial arrhythmopathy 030220 oncology & carcinogenesis Drug Binding Site Mutagenesis Site-Directed KCNK3 Drug binding site ddc:600 Anti-Arrhythmia Agents medicine.drug |
| Zdroj: | Cellular physiology and biochemistry, 52 (5), 1223-1235 Cellular Physiology and Biochemistry, Vol 52, Iss 5, Pp 1223-1235 (2019) |
| ISSN: | 1015-8987 1421-9778 |
| DOI: | 10.5445/ir/1000095214 |
| Popis: | Background/aims The two-pore-domain potassium channel TASK-1 regulates atrial action potential duration. Due to the atrium-specific expression of TASK-1 in the human heart and the functional upregulation of TASK-1 currents in atrial fibrillation (AF), TASK-1 represents a promising target for the treatment of AF. Therefore, detailed knowledge of the molecular determinants of TASK-1 inhibition may help to identify new drugs for the future therapy of AF. In the current study, the molecular determinants of TASK-1 inhibition by the potent and antiarrhythmic compound A293 (AVE1231) were studied in detail. Methods Alanine-scanning mutagenesis together with two-electrode voltage-clamp recordings were combined with in silico docking experiments. Results Here, we have identified Q126 located in the M2 segment together with L239 and N240 of the M4 segment as amino acids essential for the A293-mediated inhibition of TASK-1. These data indicate a binding site which is different to that of A1899 for which also residues of the pore signature sequence and the late M4 segments are essential. Using in silico docking experiments, we propose a binding site at the lower end of the cytosolic pore, located at the entry to lateral side fenestrations of TASK-1. Strikingly, TASK-1 inhibition by the low affinity antiarrhythmic TASK-1 blockers propafenone, amiodarone and carvedilol was also strongly diminished by mutations at this novel binding site. Conclusion We have identified the A293 binding site in the central cavity of TASK-1 and propose that this site might represent a conserved site of action for many low affinity antiarrhythmic TASK-1 blockers. |
| Databáze: | OpenAIRE |
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