Journal Article

C-terminal <i>HERG</i> (<i>LQT2</i>) mutations disrupt <i>I</i><sub>Kr</sub> channel regulation through 14-3-3ϵ

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

in Human Molecular Genetics

Volume 15, issue 19, pages 2888-2902
Published in print October 2006 | ISSN: 0964-6906
Published online August 2006 | e-ISSN: 1460-2083 | DOI:
C-terminal HERG (LQT2) mutations disrupt IKr channel regulation through 14-3-3ϵ

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β-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. β-Adrenergic stimulation of HERG channel activity is amplified and prolonged in vitro by the adaptor protein 14-3-3ϵ. 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 14-3-3ϵ. When expressed in CHO cells, the mutants produced functional HERG channels with normal kinetic properties. We now provide evidence that HERG channel regulation by 14-3-3ϵ is of physiological significance in humans. Upon co-expression with 14-3-3ϵ, mutant channels still bound 14-3-3ϵ 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 14-3-3ϵ on C-terminally truncated HERG channels demonstrate the physiological importance of coupling β-adrenergic stimulation and HERG channel activity.

Journal Article.  9067 words.  Illustrated.

Subjects: Genetics and Genomics

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