Computational Study of the Loss-of-Function Mutations in the Kv1.5 Channel Associated with Atrial Fibrillation

Rashid, M and Kuyucak, S 2018, 'Computational Study of the Loss-of-Function Mutations in the Kv1.5 Channel Associated with Atrial Fibrillation', ACS Omega, vol. 3, no. 8, pp. 8882-8890.


Document type: Journal Article
Collection: Journal Articles

Title Computational Study of the Loss-of-Function Mutations in the Kv1.5 Channel Associated with Atrial Fibrillation
Author(s) Rashid, M
Kuyucak, S
Year 2018
Journal name ACS Omega
Volume number 3
Issue number 8
Start page 8882
End page 8890
Total pages 9
Publisher American Chemical Society
Abstract Atrial fibrillation (AF) is a heart disease caused by defective ion channels in the atria, which affect the action potential (AP) duration and disturb normal heart rhythm. Rapid firing of APs in neighboring atrial cells is a common mechanism of AF, and therefore, therapeutic approaches have focused on extending the AP duration by inhibiting the K+ channels involved in repolarization. Of these, Kv1.5 that carries the IKur current is a promising target because it is expressed mainly in atria and not in ventricles. In genetic studies of AF patients, both loss-of-function and gain-of-function mutations in Kv1.5 have been identified, indicating that either decreased or increased IKur currents could trigger AF. Blocking of already downregulated Kv1.5 channels could cause AF to become chronic. Thus, a molecular-level understanding of how the loss-of-function mutations in Kv1.5 affect IKur would be useful for developing new therapeutics. Here, we perform molecular dynamics simulations to study the effect of three loss-of-function mutations in the pore domain of Kv1.5 on ion permeation. Comparison of the pore structures and ion free energies in the wild-type and mutant Kv1.5 channels indicates that conformational changes in the selectivity filter could hinder ion permeation in the mutant channels.
Subject Physical Sciences not elsewhere classified
DOI - identifier 10.1021/acsomega.8b01094
Copyright notice © 2018 American Chemical Society
ISSN 2470-1343
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