Referenced in: none

Automatically associated channels: Kv1.5

Title: Molecular determinants of Kv1.5 Channel block by diphenyl phosphine oxide-1.

Authors: Yi-Mei Du, Xiao-Xian Zhang, Dan-Na Tu, Ning Zhao, Yan-Jie Liu, Hua Xiao, Michael C Sanguinetti, Anruo Zou, Yu-hua Liao

Journal, date & volume: , 2010 Feb 22 , ,

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/20184887

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.