QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: mol.106.026203v1 70/4/1204    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Decher, N. Articles by Sanguinetti, M. C. Search for Related Content PubMed PubMed Citation Articles by Decher, N. Articles by Sanguinetti, M. C.

Binding Site of a Novel Kv1.5 Blocker: A "Foot in the Door" against Atrial Fibrillation

Nora Eccles Harrison Cardiovascular Research and Training Institute and Department of Physiology, University of Utah, Salt Lake City, Utah (N.D., P.K., T.G., M.C.S.); Institut für Normale und Pathologische Physiologie, Universität Marburg, Marburg, Germany (N.D.); and Sanofi-Aventis Deutschland GmbH, Frankfurt am Main, Germany (B.P.)

Kv1.5 channel blockers prolong atrial action potentials and may prevent atrial flutter or fibrillation without affecting ventricular repolarization. Here we characterize the mechanisms of action of 2'-{[2-(4-methoxy-phenyl)-acetylamino]-methyl}-biphenyl-2-carboxylic acid (2-pyridin-3-yl-ethyl)-amide (AVE0118) on Kv1.5 channels heterologously expressed in Xenopus laevis oocytes. Whole cell currents in oocytes were recorded using the two-microelectrode voltage clamp technique. AVE0118 blocked Kv1.5 current in oocytes with an IC₅₀ of 5.6 µM. 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 amino acids Thr479, Thr480, Val505, Ile508, Val512, and Val516 as important residues for block by AVE0118. A homology model of the pore region of Kv1.5 predicts that these six residues face toward the central cavity of the channel. In addition, mutation of two other S6 residues (Ile502 and Leu510) that are predicted to face away from the central cavity also diminished drug block. All these putative drug-binding residues are highly conserved in other Kv channels, explaining our finding that AVE0118 also blocked Kv1.3, Kv2.1, Kv3.1, and Kv4.3 channels with similar potency. Docking of AVE0118 into the inner cavity of a Kv1.5 pore homology model predicted an unusual binding mode. The drug aligned with the inner S6 -helical domain in a manner predicted to block the putative activation gate. This "foot-in-the-door" binding mode is consistent with the observation that the drug slowed the rate of current deactivation, causing a crossover of tail current traces recorded before and after drug treatment.

Address correspondence to: Michael C. Sanguinetti, Nora Eccles Harrison Cardiovascular Research and Training Institute, University of Utah, 95 South 2000 East, Salt Lake City, UT 84112. E-mail: sanguinetti{at}cvrti.utah.edu

This article has been cited by other articles:

				S. M. Schumacher, D. P. McEwen, L. Zhang, K. L. Arendt, K. M. Van Genderen, and J. R. Martens Antiarrhythmic Drug-Induced Internalization of the Atrial-Specific K+ Channel Kv1.5 Circ. Res., June 19, 2009; 104(12): 1390 - 1398. [Abstract] [Full Text] [PDF]

				I. Kopljar, A. J. Labro, E. Cuypers, H. W. B. Johnson, J. D. Rainier, J. Tytgat, and D. J. Snyders A polyether biotoxin binding site on the lipid-exposed face of the pore domain of Kv channels revealed by the marine toxin gambierol PNAS, June 16, 2009; 106(24): 9896 - 9901. [Abstract] [Full Text] [PDF]

				D. P. McEwen and J. R. Martens Antifibrillatory Agents and Potassium Channels in the Atria: Pore Block versus Channel Trafficking Mol. Interv., April 1, 2009; 9(2): 79 - 86. [Abstract] [Full Text] [PDF]

				Z. Yang, C. F. Browning, H. Hallaq, L. Yermalitskaya, J. Esker, M. R. Hall, A. J. Link, A.-J. L. Ham, M. J. McGrath, C. A. Mitchell, et al. Four and a half LIM protein 1: a partner for KCNA5 in human atrium Cardiovasc Res, June 1, 2008; 78(3): 449 - 457. [Abstract] [Full Text] [PDF]

				C. P. Regan, L. Kiss, G. L. Stump, C. J. McIntyre, D. C. Beshore, N. J. Liverton, C. J. Dinsmore, and J. J. Lynch Jr. Atrial Antifibrillatory Effects of Structurally Distinct IKur Blockers 3-[(Dimethylamino)methyl]-6-methoxy-2-methyl-4-phenylisoquinolin-1(2H)-one and 2-Phenyl-1,1-dipyridin-3-yl-2-pyrrolidin-1-yl-ethanol in Dogs with Underlying Heart Failure J. Pharmacol. Exp. Ther., January 1, 2008; 324(1): 322 - 330. [Abstract] [Full Text] [PDF]

				J. Eldstrom, Z. Wang, H. Xu, M. Pourrier, A. Ezrin, K. Gibson, and D. Fedida The Molecular Basis of High-Affinity Binding of the Antiarrhythmic Compound Vernakalant (RSD1235) to Kv1.5 Channels Mol. Pharmacol., December 1, 2007; 72(6): 1522 - 1534. [Abstract] [Full Text] [PDF]

				S. J. Fountain, A. Cheong, J. Li, N. Y. Dondas, F. Zeng, I. C. Wood, and D. J. Beech Kv1.5 potassium channel gene regulation by Sp1 transcription factor and oxidative stress Am J Physiol Heart Circ Physiol, November 1, 2007; 293(5): H2719 - H2725. [Abstract] [Full Text] [PDF]