(Circulation. 2005;112:1376-1378.)
© 2005 American Heart Association, Inc.
Editorial |
From the Division of Clinical Pharmacology, Departments of Medicine and Pharmacology, Vanderbilt University School of Medicine, Nashville, Tenn.
Correspondence to Dan M. Roden, MD, Director, Oates Institute for Experimental Therapeutics, Vanderbilt University School of Medicine, 532 Medical Research Building I, Nashville, TN 37232. E-mail dan.roden{at}vanderbilt.edu
Key Words: Editorials arrhythmia ion channels potassium repolarization
| Introduction |
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See p 1384 and 1392
| Separating IK Into IKr and IKs in Heart |
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The physiological and pharmacological separation of IKr and IKs were followed in the mid-1990s by the cloning of the genes whose expression generates these currents, and the identification of mutations in those genes as the commonest causes for the congenital long QT syndrome.911 Expression of HERG (now also known as KCNH2) is sufficient to recapitulate most properties of IKr, although ancillary function-modifying subunits have been proposed.12,13 By contrast, recapitulation of IKs requires coexpression not only of the gene encoding the pore-forming subunit, KCNQ1 (formerly known as KvLQT1), but also an important function-modifying protein, termed KCNE1 (or minK),14,15 which was initially cloned from a rat kidney cDNA library.16
| IKr Block Causes Torsade de Pointes, But Not Always |
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| At First Glance, IKs Does Not Seem Large in Human Ventricular Myocytes |
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| What Does KCNE1 Do to K+ Current to Make It IKs? |
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Silva and Rudy have explored new state models for KCNQ1 and for KCNQ1 + KCNE1 to address this issue. The simplest model to explain the behavior of an ion channel is one in which the channel can occupy 1 of 2 states, closed or open, with state transitions described by individual rate constants. The observation that IKs activation occurs with depolarization, but only after a delay, suggests that the channel may move through multiple closed states before opening during a depolarization.29 Silva and Rudy used physiological data obtained from multiple previous reports to construct a much more complex view of KCNQ1 behavior alone and in presence of KCNE1 to generate IKs. The simulations strongly suggest that IKs accumulation at rapid rates is not caused by slow deactivation but rather by preferential occupancy of the channel in "proximal" closed states, very near the open one, at fast rates. When the channel exists in these proximal closed states, IKs can open with a minimal delay after a depolarization and rapidly become rather large. A particularly intriguing observation is that KCNQ1 alone cannot prevent an arrhythmogenic, pause-dependent early afterdepolarization, whereas IKs, by activating during the plateau potential, can. In this way, repolarization reserve is generated by coexpression of KCNE1 with KCNQ1. "States" in models such as these represent either biophysical abstractions or, conceivably, individual conformations of the dynamic behaviors of these proteins. As Silva and Rudy are at pains to point out, although the results from the model are provocative, interesting, and physiologically rational, they are hypothesis-generating until additional physiological studies, which they even outline, address them.
| Approaches to the Study of Complex Biological Systems |
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| Acknowledgments |
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| Footnotes |
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| References |
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