In a study appearing online on July 14 in advance of print publication of the August 1 issue of the Journal of Clinical Investigation, Dan Roden and colleagues from Vanderbilt University propose a novel mechanism of modulation of drug block of this heart ion channel -– KCNA5 – that is becoming increasingly important as a potential drug target. The authors find that the polymorphism induces a structural change that interferes with drug access to the pore.
The researchers engineered channels with the polymorphism and found that the antiarrhythmic drugs have different access to the putative blocking site in the channel, and that this access is strongly regulated by the presence or absence of a structural motif in the C-terminus. Thus, the variant channel is distinguishable from wild-type only with drug exposure, and this variable drug access to its target binding site is through a mechanism has not previously been reported for ion channels.
Title: Human cardiac potassium channel DNA polymorphism modulates access to drug-binding site and causes drug resistance.
AUTHOR CONTACT:
Dan M. Roden
Vanderbilt University School Of Medicine, Nashville, TN USA
Phone: 615-322-0067; Fax: 615-343-4522; E-mail: dan.roden@vanderbilt.edu
View the PDF of this article at: https://www.the-jci.org/article.php?id=23741
Journal
Journal of Clinical Investigation