1. Molecular determinants of Kv1.5 channel block by diphenyl phosphine oxide-1
- Author
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Yan jie Liu, Xiao xian Zhang, Yu-Hua Liao, Michael C. Sanguinetti, Hua Xiao, Ning Zhao, Anruo Zou, Dan na Tu, and Yimei Du
- Subjects
Threonine ,Patch-Clamp Techniques ,Phosphines ,Voltage clamp ,Xenopus ,Plasma protein binding ,Inhibitory Concentration 50 ,Kv1.5 Potassium Channel ,Xenopus laevis ,Leucine ,Atrial Fibrillation ,Animals ,Humans ,Channel blocker ,Computer Simulation ,Patch clamp ,Binding site ,Isoleucine ,Molecular Biology ,biology ,Chemistry ,Mutagenesis ,biology.organism_classification ,Potassium channel ,Electrophysiology ,Anesthesia ,Biophysics ,Oocytes ,Cardiology and Cardiovascular Medicine ,Protein Binding - Abstract
Kv1.5 channels conduct the ultra-rapid delayed rectifier current (I(Kur)) 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 IC(50) of 0.78+/-0.12 microM 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 Kvbeta1.3.
- Published
- 2009