Atrial fibrillation is an irregular heartbeat (arrhythmia) in which the atria, or upper chambers of the heart, beat quickly and inconsistently. Expression of potassium channel KCNA5 is confined to cells in the atria and not the ventricle, making it a target for the development of drugs to treat atrial fibrillation. Polymorphisms in KCNA5 have been identified, which make the potassium channel less sensitive to blockade by antiarrhythmic drugs, but appear otherwise indistinguishable from normal potassium channels.
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.
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Journal of Clinical Investigation
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