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Human Molecular Genetics Advance Access published online on August 21, 2006
Human Molecular Genetics, doi:10.1093/hmg/ddl230
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© The Author 2006. Published by Oxford University Press. All rights reserved
Received April 1, 2006
Revised August 10, 2006
Accepted August 10, 2006

Article

C-terminal HERG (LQT2) mutations disrupt IKr channel regulation through 14-3-3{varepsilon}

Chi-un Choe 1, Eric Schulze-Bahr 2, Axel Neu 3, Jun Xu 4, Zheng I. Zhu 4, Kathrin Sauter 1, Robert Bähring 1, Silvia Priori 5, Pascale Guicheney 6, Gerold Mönnig 2, Carlo Neapolitano 5, Jan Heidemann 7, Colleen E. Clancy 4, Olaf Pongs 1, and Dirk Isbrandt 8 *

1 Institute for Neural Signal Transduction, ZMNH, University Hospital Hamburg-Eppendorf, Germany
2 Leibniz Institute for Arteriosclerosis Research (LIFA) at the University of Münster, Germany; Department of Cardiology and Angiology of the University Hospital of Münster, Germany
3 Institute for Neural Signal Transduction, ZMNH, University Hospital Hamburg-Eppendorf, Germany; Department of Pediatrics, University Hospital Hamburg-Eppendorf, Germany
4 Department of Physiology and Biophysics, Institute for Computational Biomedicine, Weill Medical College of Cornell University, New York, NY, USA
5 Fondazione Salvatore Maugeri, IRCCS, Pavia, Italy
6 INSERM U523, Institut de Myologie, Groupe Hospitalier Pitié Salpêtrière, Paris, France
7 Department of Medicine B, University of Münster, Germany
8 Zentrum für Molekulare Neurobiologie Hamburg (ZMNH), University Hospital Hamburg-Eppendorf, Institut für Neurale Signalverarbeitung, Martinistrasse 52, 20246 Hamburg, Germany

* To whom correspondence should be addressed.
Dirk Isbrandt, E-mail: dirk.isbrandt{at}isbrandtlab.org


  Abstract

Beta-adrenergic receptor-mediated cAMP or protein kinase A (PKA)-dependent modulation of cardiac potassium currents controls ventricular action potential duration at faster heart rates. HERG (KCNH2) gene mutations are associated with congenital long-QT syndrome (LQT2) and affect IKr activity, a key determinant in ventricular repolarization. Physical activity or emotional stress often triggers lethal arrhythmias in LQT2 patients. {beta}-Adrenergic stimulation of HERG channel activity is amplified and prolonged in vitro by the adaptor protein 14-3-3{varepsilon}. In LQT2 families, we identified three novel heterozygous HERG mutations (G965X, R1014PfsX39, V1038AfsX21) in the C-terminus that led to protein truncation and loss of a PKA phosphorylation site required for binding of 14-3-3{varepsilon}. When expressed in CHO cells, the mutants produced functional HERG channels with normal kinetic properties. We now provide evidence that HERG channel regulation by 14-3-3{varepsilon} is of physiological significance in humans. Upon coexpression with 14-3-3{varepsilon}, mutant channels still bound 14-3-3{varepsilon} but did not respond with a hyperpolarizing shift in voltage dependence as seen in wild-type channels. Coexpression experiments of wild-type and mutant channels revealed dominant-negative behavior of all three HERG mutations. Simulations of the effects of sympathetic stimulation of HERG channel activity on the whole-cell action potential suggested a role in rate-dependent control of action potential duration and an impaired ability of mutant cardiac myocytes to respond to a triggered event or an ectopic beat. In summary, the attenuated functional effects of 14-3-3{varepsilon} on C-terminally truncated HERG channels demonstrate the physiological importance of coupling {beta}-adrenergic stimulation and HERG channel activity.


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