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

38 Citations (Scopus)

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

Fingerprint

Action Potentials
Cyclic AMP-Dependent Protein Kinases
Adrenergic Agents
Mutation
14-3-3 Proteins
Long QT Syndrome
Aptitude
CHO Cells
Psychological Stress
Cardiac Myocytes
Adrenergic Receptors
Cardiac Arrhythmias
Potassium
Heart Rate
Binding Sites
Phosphorylation
Exercise
Genes
Proteins
In Vitro Techniques

ASJC Scopus subject areas

  • Genetics

Cite this

Choe, C. U., Schulze-Bahr, E., Neu, A., Xu, J., Zhu, Z. I., Sauter, K., ... 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

C-terminal HERG (LQT2) mutations disrupt IKr channel regulation through 14-3-3ε. / Choe, Chi Un; Schulze-Bahr, Eric; Neu, Axel; Xu, Jun; Zhu, Zheng I.; Sauter, Kathrin; Bähring, Robert; Priori, Silvia; Guicheney, Pascale; Mönnig, Gerold; Neapolitano, Carlo; Heidemann, Jan; Clancy, Colleen E.; Pongs, Olaf; Isbrandt, Dirk.

In: Human Molecular Genetics, Vol. 15, No. 19, 01.10.2006, p. 2888-2902.

Research output: Contribution to journalArticle

Choe, CU, Schulze-Bahr, E, Neu, A, Xu, J, Zhu, ZI, Sauter, K, Bähring, R, Priori, S, Guicheney, P, Mönnig, G, Neapolitano, C, Heidemann, J, Clancy, CE, Pongs, O & Isbrandt, D 2006, 'C-terminal HERG (LQT2) mutations disrupt IKr channel regulation through 14-3-3ε', Human Molecular Genetics, vol. 15, no. 19, pp. 2888-2902. https://doi.org/10.1093/hmg/ddl230
Choe CU, Schulze-Bahr E, Neu A, Xu J, Zhu ZI, Sauter K et al. C-terminal HERG (LQT2) mutations disrupt IKr channel regulation through 14-3-3ε. Human Molecular Genetics. 2006 Oct 1;15(19):2888-2902. https://doi.org/10.1093/hmg/ddl230
Choe, Chi Un ; Schulze-Bahr, Eric ; Neu, Axel ; Xu, Jun ; Zhu, Zheng I. ; Sauter, Kathrin ; Bähring, Robert ; Priori, Silvia ; Guicheney, Pascale ; Mönnig, Gerold ; Neapolitano, Carlo ; Heidemann, Jan ; Clancy, Colleen E. ; Pongs, Olaf ; Isbrandt, Dirk. / C-terminal HERG (LQT2) mutations disrupt IKr channel regulation through 14-3-3ε. In: Human Molecular Genetics. 2006 ; Vol. 15, No. 19. pp. 2888-2902.
@article{8991488a15de4c0abd3d665a7ca2f0e7,
title = "C-terminal HERG (LQT2) mutations disrupt IKr channel regulation through 14-3-3ε",
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.",
author = "Choe, {Chi Un} and Eric Schulze-Bahr and Axel Neu and Jun Xu and Zhu, {Zheng I.} and Kathrin Sauter and Robert B{\"a}hring and Silvia Priori and Pascale Guicheney and Gerold M{\"o}nnig and Carlo Neapolitano and Jan Heidemann and Clancy, {Colleen E.} and Olaf Pongs and Dirk Isbrandt",
year = "2006",
month = "10",
day = "1",
doi = "10.1093/hmg/ddl230",
language = "English",
volume = "15",
pages = "2888--2902",
journal = "Human Molecular Genetics",
issn = "0964-6906",
publisher = "Oxford University Press",
number = "19",

}

TY - JOUR

T1 - C-terminal HERG (LQT2) mutations disrupt IKr channel regulation through 14-3-3ε

AU - Choe, Chi Un

AU - Schulze-Bahr, Eric

AU - Neu, Axel

AU - Xu, Jun

AU - Zhu, Zheng I.

AU - Sauter, Kathrin

AU - Bähring, Robert

AU - Priori, Silvia

AU - Guicheney, Pascale

AU - Mönnig, Gerold

AU - Neapolitano, Carlo

AU - Heidemann, Jan

AU - Clancy, Colleen E.

AU - Pongs, Olaf

AU - Isbrandt, Dirk

PY - 2006/10/1

Y1 - 2006/10/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=33749001960&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=33749001960&partnerID=8YFLogxK

U2 - 10.1093/hmg/ddl230

DO - 10.1093/hmg/ddl230

M3 - Article

VL - 15

SP - 2888

EP - 2902

JO - Human Molecular Genetics

JF - Human Molecular Genetics

SN - 0964-6906

IS - 19

ER -