title: Molecular determinants of Kv1.5 channel block by diphenyl phosphine oxide-1.
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.
authors.affiliation: Research Center of Ion Channelopathy, Institute of Cardiovascular Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Ave, Wuhan 430022, China.
authors.forename: Yi-mei
authors.initials: YM
authors.lastname: Du
authors.forename: Xiao-xian
authors.initials: XX
authors.lastname: Zhang
authors.forename: Dan-na
authors.initials: DN
authors.lastname: Tu
authors.forename: Ning
authors.initials: N
authors.lastname: Zhao
authors.forename: Yan-jie
authors.initials: YJ
authors.lastname: Liu
authors.forename: Hua
authors.initials: H
authors.lastname: Xiao
authors.forename: Michael C
authors.initials: MC
authors.lastname: Sanguinetti
authors.forename: Anruo
authors.initials: A
authors.lastname: Zou
authors.forename: Yu-hua
authors.initials: YH
authors.lastname: Liao
mesh_terms: D000818:Animals; D001281:Atrial Fibrillation / Q000378:metabolism; D003198:Computer Simulation; D004594:Electrophysiology / Q000379:methods; D006801:Humans; D020128:Inhibitory Concentration 50; D007532:Isoleucine / Q000737:chemistry; D051666:Kv1.5 Potassium Channel / Q000378:metabolism*; D007930:Leucine / Q000737:chemistry; D009865:Oocytes / Q000378:metabolism; D018408:Patch-Clamp Techniques; D010720:Phosphines / Q000378:metabolism*; D011485:Protein Binding; D013912:Threonine / Q000737:chemistry; D014982:Xenopus laevis
chemical_list: C507236:(2-isopropyl-5-methylcyclohexyl) diphenylphosphine oxide; D051666:Kv1.5 Potassium Channel; D010720:Phosphines; D007532:Isoleucine; D013912:Threonine; D007930:Leucine