Human Molecular Genetics Advance Access originally published online on August 21, 2006
Human Molecular Genetics 2006 15(19):2888-2902; doi:10.1093/hmg/ddl230
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C-terminal HERG (LQT2) mutations disrupt IKr channel regulation through 14-3-3
1 Institute for Neural Signal Transduction, ZMNH , 2 Department of Pediatrics, University Hospital Hamburg-Eppendorf, Martinistr. 52, 20246 Hamburg, Germany, 3 Leibniz Institute for Arteriosclerosis Research (LIFA) , 4 Department of Cardiology and Angiology , 5 Department of Medicine B, University of Münster, Germany, 6 Department of Physiology and Biophysics, Institute for Computational Biomedicine, Weill Medical College of Cornell University, New York, NY, USA, 7 Fondazione Salvatore Maugeri, IRCCS, Pavia, Italy, 8 INSERM U582, Institut de Myologie, Groupe Hospitalier Pitié Salpêtrière, Paris, France and 9 Université Pierre et Marie Curie-Paris6, UMR S582, IFR14, Paris, France
* To whom correspondence should be addressed. Tel: +49 40428036650; Fax: +49 40428036643; Email: dirk.isbrandt{at}isbrandtlab.org
Received April 1, 2006; Revised July 3, 2006; Accepted August 10, 2006
ß-Adrenergic receptor-mediated cAMP or protein kinase A (PKA)-dependent modulation of cardiac potassium currents controls ventricular action potential duration (APD) 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. ß-Adrenergic stimulation of HERG channel activity is amplified and prolonged in vitro by the adaptor protein 14-3-3
. 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. 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 is of physiological significance in humans. Upon co-expression with 14-3-3, mutant channels still bound 14-3-3 but did not respond with a hyperpolarizing shift in voltage dependence as seen in wild-type channels. Co-expression 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 APD 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 on C-terminally truncated HERG channels demonstrate the physiological importance of coupling ß-adrenergic stimulation and HERG channel activity.
The authors wish it to be known that, in their opinion, the first three authors should be regarded as joint First Authors.
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