Genetic Disruption of Kir6.2, the Pore-Forming Subunit of ATP-Sensitive K+ Channel, Predisposes to Catecholamine-Induced Ventricular Dysrhythmia

  1. Xiao-Ke Liu1,
  2. Satsuki Yamada1,
  3. Garvan C. Kane1,
  4. Alexey E. Alekseev1,
  5. Denice M. Hodgson1,
  6. Fearghas O’Cochlain1,
  7. Arshad Jahangir1,
  8. Takashi Miki2,
  9. Susumu Seino2 and
  10. Andre Terzic1
  1. 1Division of Cardiovascular Diseases, Department of Medicine, Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic College of Medicine, Rochester, Minnesota
  2. 2Division of Cellular and Molecular Medicine, Kobe University Graduate School of Medicine, Kobe, Japan
  1. Address correspondence and reprint requests to Andre Terzic, MD, PhD, Guggenheim 7, Mayo Clinic, Rochester, MN 55905. E-mail: terzic.andre{at}mayo.edu

Abstract

Metabolic-sensing ATP-sensitive K+ channels (KATP channels) adjust membrane excitability to match cellular energetic demand. In the heart, KATP channel activity has been linked to homeostatic shortening of the action potential under stress, yet the requirement of channel function in securing cardiac electrical stability is only partially understood. Here, upon catecholamine challenge, disruption of KATP channels, by genetic deletion of the pore-forming Kir6.2 subunit, produced defective cardiac action potential shortening, predisposing the myocardium to early afterdepolarizations. This deficit in repolarization reserve, demonstrated in Kir6.2-knockout hearts, translated into a high risk for induction of triggered activity and ventricular dysrhythmia. Thus, intact KATP channel function is mandatory for adequate repolarization under sympathetic stress providing electrical tolerance against triggered arrhythmia.

Footnotes

  • This article is based on a presentation at a symposium. The symposium and the publication of this article were made possible by an unrestricted educational grant from Servier.

    • Accepted May 18, 2004.
    • Received March 12, 2004.
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