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.
A1899
A293
AVE1231
Atrial arrhythmopathy
Atrial cardiomyopathy
Atrial fibrillation
Drug binding site
K2P3.1
KCNK3
TASK-1
Two-pore-domain potassium channels
Journal
Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology
ISSN: 1421-9778
Titre abrégé: Cell Physiol Biochem
Pays: Germany
ID NLM: 9113221
Informations de publication
Date de publication:
2019
2019
Historique:
received:
21
08
2018
accepted:
30
01
2019
entrez:
20
4
2019
pubmed:
20
4
2019
medline:
3
5
2019
Statut:
ppublish
Résumé
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. Alanine-scanning mutagenesis together with two-electrode voltage-clamp recordings were combined with in silico docking experiments. 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. 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.
Sections du résumé
BACKGROUND/AIMS
OBJECTIVE
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
METHODS
Alanine-scanning mutagenesis together with two-electrode voltage-clamp recordings were combined with in silico docking experiments.
RESULTS
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
CONCLUSIONS
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.
Substances chimiques
Anti-Arrhythmia Agents
0
Nerve Tissue Proteins
0
Potassium Channels, Tandem Pore Domain
0
potassium channel subfamily K member 3
1HQ3YCN4GS
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
1223-1235Subventions
Organisme : University of Heidelberg, Faculty of Medicine
ID : Rahel Goitein-Straus Scholarship and Olympia-Morata Scholarship
Pays : Germany
Organisme : German Center for Cardiovascular Research (DZHK)
ID : Excellence Grant
Pays : Germany
Organisme : German Cardiac Society (DGK)
ID : DGK082018 and Otto-Hess Fellowship
Pays : Germany
Organisme : German Heart Foundation /German Foundation of Heart Research
ID : F/41/15 and Kaltenbach Scholarship
Pays : Germany
Organisme : Fondecyt Grant
ID : 1191133
Pays : Chile
Organisme : Millennium Nucleus of Ion Channels Associated Diseases (MiNICAD)
Pays : Chile
Organisme : German Research Foundation (DFG)
ID : SCHM 3358/1-1, DE1482-4/1
Pays : Germany
Informations de copyright
© Copyright by the Author(s). Published by Cell Physiol Biochem Press.
Déclaration de conflit d'intérêts
The authors declare that they have no conflict of interests.