کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
10954180 | 1097846 | 2010 | 10 صفحه PDF | دانلود رایگان |
عنوان انگلیسی مقاله ISI
Molecular determinants of Kv1.5 channel block by diphenyl phosphine oxide-1
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کلمات کلیدی
موضوعات مرتبط
علوم زیستی و بیوفناوری
بیوشیمی، ژنتیک و زیست شناسی مولکولی
بیولوژی سلول
پیش نمایش صفحه اول مقاله
چکیده انگلیسی
Kv1.5 channels conduct the ultra-rapid delayed rectifier current (IKur) that contributes to action potential repolarization of human atrial myocytes. Block of these channels has been proposed as a treatment for atrial arrhythmias. Diphenyl phosphine oxide-1 (DPO-1) is a novel and potent inhibitor of Kv1.5 potassium channels. The present study was undertaken to characterize the mechanisms and molecular determinants of channel block by DPO-1. Experiments were carried out on wild-type and mutant Kv1.5 channels expressed in Xenopus laevis oocytes using the standard two microelectrode voltage clamp technique. DPO-1 blocked Kv1.5 current in oocytes with an IC50 of 0.78 ± 0.12 μM at + 40 mV. Block was enhanced by higher rates of stimulation, consistent with preferential binding of the drug to the open state of the channel. Ala-scanning mutagenesis of the pore domain of Kv1.5 identified the residues Thr480, Leu499, Leu506, Ile508, Leu510 and Val514 as components of the putative binding site for DPO-1, partially overlapping the site previously defined for the Kv1.5 channel blockers AVE0118 and S0100176. Block of Kv1.5 by DPO-1 was significantly reduced in the presence of Kvβ1.3.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Journal of Molecular and Cellular Cardiology - Volume 48, Issue 6, June 2010, Pages 1111-1120
Journal: Journal of Molecular and Cellular Cardiology - Volume 48, Issue 6, June 2010, Pages 1111-1120
نویسندگان
Yi-mei Du, Xiao-xian Zhang, Dan-na Tu, Ning Zhao, Yan-jie Liu, Hua Xiao, Michael C. Sanguinetti, Anruo Zou, Yu-hua Liao,