This Article Full Text Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Kiehn, J. Articles by Brown, A.M. Search for Related Content PubMed PubMed Citation Articles by Kiehn, J. Articles by Brown, A.M.

(Circulation Research. 1995;77:1151-1155.)
© 1995 American Heart Association, Inc.

Articles

Cloned Human Inward Rectifier K⁺ Channel as a Target for Class III Methanesulfonanilides

J. Kiehn, B. Wible, E. Ficker, M. Taglialatela, A.M. Brown

From the Rammelkamp Center for Research, MetroHealth Campus, Case Western Reserve University, Cleveland, Ohio; the Department of Physiology, Baylor College of Medicine, Houston, Tex; and the Department of Neuroscience Section of Pharmacology (M.T.), Second School of Medicine, University of Naples, Italy.

Correspondence to A.M. Brown, Rammelkamp Center, 2500 MetroHealth Drive, Cleveland, OH 44109-1998.

Abstract Methanesulfonanilide derivatives such as dofetilide are members of the widely used Class III group of cardiac antiarrhythmic drugs. A methanesulfonanilide-sensitive cardiac current has been identified as I_Kr, the rapidly activating component of the repolarizing outward cardiac K⁺ current, I_K. I_Kr may be encoded by the human ether-related gene (hERG), which belongs to the family of voltage-dependent K⁺ (K_v) channels having six putative transmembrane segments. The hERG also expresses an inwardly rectifying, methanesulfonanilide-sensitive K⁺ current. Here we show that hIRK, a member of the two-transmembrane-segment family of inward K⁺ rectifiers that we have cloned from human heart, is a target for dofetilide. hIRK currents, expressed heterologously in Xenopus oocytes, are blocked by dofetilide at submicromolar concentrations (IC₅₀=533 nmol/L at 40 mV and 20°C). The drug has no significant blocking effect on the human cardiac K_v channels hK_v1.2, hK_v1.4, hK_v1.5, or hK_v2.1. The block is voltage dependent, use dependent, and shortens open times in a manner consistent with open-channel block. While steady state block is strongest at depolarized potentials, recovery from block is very slow even at hyperpolarized potentials (tau=1.17 seconds at -80 mV). Thus, block of hIRK may persist during diastole and might thereby affect cardiac excitability.

Key Words: human inward rectifier K⁺ channel • Class III antiarrhythmic drugs • dofetilide • I_Kr

This article has been cited by other articles:

				W. Hirdes, L. F. Horowitz, and B. Hille Muscarinic modulation of erg potassium current J. Physiol., August 15, 2004; 559(1): 67 - 84. [Abstract] [Full Text] [PDF]

				F. S. Cayabyab, F. W. L. Tsui, and L. C. Schlichter Modulation of the ERG K+ Current by the Tyrosine Phosphatase, SHP-1 J. Biol. Chem., December 6, 2002; 277(50): 48130 - 48138. [Abstract] [Full Text] [PDF]

				C. A. Karle, E. Zitron, W. Zhang, G. Wendt-Nordahl, S. Kathofer, D. Thomas, B. Gut, E. Scholz, C.-F. Vahl, H. A. Katus, et al. Human Cardiac Inwardly-Rectifying K+ Channel Kir2.1b Is Inhibited by Direct Protein Kinase C-Dependent Regulation in Human Isolated Cardiomyocytes and in an Expression System Circulation, September 17, 2002; 106(12): 1493 - 1499. [Abstract] [Full Text] [PDF]

				J.-B. Park, H. Choe, Y.-K. Lee, K.-C. Ha, K.-S. Rhee, J.-K. Ko, C.-U. Joo, S.-W. Chae, and Y.-G. Kwak Open Channel Block by KCB-328 [1-(2-Amino-4-methanesulfonamidophenoxy)-2-[N-(3,4-dimethoxyphenethyl)-N-methylamino]ethane Hydrochloride] of the Heterologously Expressed Human Ether-a-go-go-Related Gene K+ Channels J. Pharmacol. Exp. Ther., July 1, 2002; 302(1): 314 - 319. [Abstract] [Full Text] [PDF]

				C. A Karle, V. A.W Kreye, D. Thomas, K. Rockl, S. Kathofer, W. Zhang, and J. Kiehn Antiarrhythmic drug carvedilol inhibits HERG potassium channels Cardiovasc Res, February 1, 2001; 49(2): 361 - 370. [Abstract] [Full Text] [PDF]

				K. S. Lee and E. W. Lee Ionic Mechanism of Ibutilide in Human Atrium: Evidence for a Drug-Induced Na+ Current Through a Nifedipine Inhibited Inward Channel J. Pharmacol. Exp. Ther., July 1, 1998; 286(1): 9 - 22. [Abstract] [Full Text]

				J. Kiehn, A. E. Lacerda, B. Wible, and A. M. Brown Molecular Physiology and Pharmacology of HERG: Single-Channel Currents and Block by Dofetilide Circulation, November 15, 1996; 94(10): 2572 - 2579. [Abstract] [Full Text]

				Z. Wang, J. Kiehn, Q. Yang, A. M. Brown, and B. A. Wible Comparison of Binding and Block Produced by Alternatively Spliced Kvbeta 1 Subunits J. Biol. Chem., November 8, 1996; 271(45): 28311 - 28317. [Abstract] [Full Text] [PDF]