C-terminal HERG (LQT2) mutations disrupt IKr 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, Dirk Isbrandt

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish
Pages (from-to)2888-2902
Number of pages15
JournalHuman Molecular Genetics
Volume15
Issue number19
DOIs
Publication statusPublished - Oct 1 2006

ASJC Scopus subject areas

  • Genetics

Fingerprint Dive into the research topics of 'C-terminal HERG (LQT2) mutations disrupt I<sub>Kr</sub> channel regulation through 14-3-3ε'. Together they form a unique fingerprint.

  • Cite this

    Choe, C. U., Schulze-Bahr, E., Neu, A., Xu, J., Zhu, Z. I., Sauter, K., Bähring, R., Priori, S., Guicheney, P., Mönnig, G., Neapolitano, C., Heidemann, J., Clancy, C. E., Pongs, O., & Isbrandt, D. (2006). C-terminal HERG (LQT2) mutations disrupt IKr channel regulation through 14-3-3ε. Human Molecular Genetics, 15(19), 2888-2902. https://doi.org/10.1093/hmg/ddl230