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Pathways of HERG inactivation

Pathways of HERG inactivation Abstract The rapid, repolarizing K + current in cardiomyocytes ( I Kr ) has unique inwardly rectifying properties that contribute importantly to the downstroke of the cardiac action potential. The human ether-à-go-go -related gene ( HERG ) expresses a macroscopic current virtually identical to I Kr , but a description of the single-channel properties that cause rectification is lacking. For this reason we measured single-channel and macropatch currents heterologously expressed by HERG in Xenopus oocytes. Our experiments had two main findings. First, the single-channel current-voltage relation showed inward rectification, and conductance was 9.7 pS at −100 mV and 3.9 pS at 100 mV when measured in symmetrical 100 mM K + solutions. Second, single channels frequently showed no openings during depolarization but nevertheless revealed bursts of openings during repolarization. This type of gating may explain the inward rectification of HERG currents. To test this hypothesis, we used a three-closed state kinetics model and obtained rate constants from fits to macropatch data. Results from the model are consistent with rapid inactivation from closed states as a significant source of HERG rectification. rapid repolarizing cardiac potassium current kinetics activation Footnotes Address for reprint requests and other correspondence: A. E. Lacerda, Rammelkamp Center, 2500 MetroHealth Drive, Cleveland, OH 44109-1998 (E-mail: alacerda@research.mhmc.org ). We thank Dr. G. Kirsch for comments on the manuscript, P. Kiehn and Dr. W. Q. Dong for technical assistance, and Dr. M. Keating for providing the HERG clone. This study was supported by a Deutsche Forschungsgemeinschaft Grant (to J. Kiehn) and National Heart, Lung, and Blood Institute Grants HL-37044 and HL-36930 (to A. M. Brown). Present address of J. Kiehn: Dept. of Cardiology, Medical Univ. Hospital, Bergheimerstr. 58, 69115 Heidelberg, Germany. The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “ advertisement ” in accordance with 18 U.S.C. §1734 solely to indicate this fact. Copyright © 1999 the American Physiological Society http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png AJP - Heart and Circulatory Physiology The American Physiological Society

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Publisher
The American Physiological Society
Copyright
Copyright © 2011 the American Physiological Society
ISSN
0363-6135
eISSN
1522-1539
Publisher site
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Abstract

Abstract The rapid, repolarizing K + current in cardiomyocytes ( I Kr ) has unique inwardly rectifying properties that contribute importantly to the downstroke of the cardiac action potential. The human ether-à-go-go -related gene ( HERG ) expresses a macroscopic current virtually identical to I Kr , but a description of the single-channel properties that cause rectification is lacking. For this reason we measured single-channel and macropatch currents heterologously expressed by HERG in Xenopus oocytes. Our experiments had two main findings. First, the single-channel current-voltage relation showed inward rectification, and conductance was 9.7 pS at −100 mV and 3.9 pS at 100 mV when measured in symmetrical 100 mM K + solutions. Second, single channels frequently showed no openings during depolarization but nevertheless revealed bursts of openings during repolarization. This type of gating may explain the inward rectification of HERG currents. To test this hypothesis, we used a three-closed state kinetics model and obtained rate constants from fits to macropatch data. Results from the model are consistent with rapid inactivation from closed states as a significant source of HERG rectification. rapid repolarizing cardiac potassium current kinetics activation Footnotes Address for reprint requests and other correspondence: A. E. Lacerda, Rammelkamp Center, 2500 MetroHealth Drive, Cleveland, OH 44109-1998 (E-mail: alacerda@research.mhmc.org ). We thank Dr. G. Kirsch for comments on the manuscript, P. Kiehn and Dr. W. Q. Dong for technical assistance, and Dr. M. Keating for providing the HERG clone. This study was supported by a Deutsche Forschungsgemeinschaft Grant (to J. Kiehn) and National Heart, Lung, and Blood Institute Grants HL-37044 and HL-36930 (to A. M. Brown). Present address of J. Kiehn: Dept. of Cardiology, Medical Univ. Hospital, Bergheimerstr. 58, 69115 Heidelberg, Germany. The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “ advertisement ” in accordance with 18 U.S.C. §1734 solely to indicate this fact. Copyright © 1999 the American Physiological Society

Journal

AJP - Heart and Circulatory PhysiologyThe American Physiological Society

Published: Jul 1, 1999

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