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C-terminal HERG (LQT2) mutations disrupt IKr channel regulation through 14-3-3epsilon.

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C-terminal HERG (LQT2) mutations disrupt IKr channel regulation through 14-3-3epsilon. / 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: HUM MOL GENET, Vol. 15, No. 19, 19, 2006, p. 2888-2902.

Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review

Harvard

Choe, C-U, 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 14-3-3epsilon.', HUM MOL GENET, vol. 15, no. 19, 19, pp. 2888-2902. <http://www.ncbi.nlm.nih.gov/pubmed/16923798?dopt=Citation>

APA

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 14-3-3epsilon. HUM MOL GENET, 15(19), 2888-2902. [19]. http://www.ncbi.nlm.nih.gov/pubmed/16923798?dopt=Citation

Vancouver

Choe C-U, Schulze-Bahr E, Neu A, Xu J, Zhu ZI, Sauter K et al. C-terminal HERG (LQT2) mutations disrupt IKr channel regulation through 14-3-3epsilon. HUM MOL GENET. 2006;15(19):2888-2902. 19.

Bibtex

@article{895cc8ce4d1c4b27bc1ce475bc58a586,
title = "C-terminal HERG (LQT2) mutations disrupt IKr channel regulation through 14-3-3epsilon.",
abstract = "Beta-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. Beta-adrenergic stimulation of HERG channel activity is amplified and prolonged in vitro by the adaptor protein 14-3-3epsilon. 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 14-3-3epsilon. When expressed in CHO cells, the mutants produced functional HERG channels with normal kinetic properties. We now provide evidence that HERG channel regulation by 14-3-3epsilon is of physiological significance in humans. Upon co-expression with 14-3-3epsilon, mutant channels still bound 14-3-3epsilon 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 14-3-3epsilon on C-terminally truncated HERG channels demonstrate the physiological importance of coupling beta-adrenergic stimulation and HERG channel activity.",
author = "Chi-Un Choe 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",
language = "Deutsch",
volume = "15",
pages = "2888--2902",
journal = "HUM MOL GENET",
issn = "0964-6906",
publisher = "Oxford University Press",
number = "19",

}

RIS

TY - JOUR

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

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

Y1 - 2006

N2 - Beta-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. Beta-adrenergic stimulation of HERG channel activity is amplified and prolonged in vitro by the adaptor protein 14-3-3epsilon. 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 14-3-3epsilon. When expressed in CHO cells, the mutants produced functional HERG channels with normal kinetic properties. We now provide evidence that HERG channel regulation by 14-3-3epsilon is of physiological significance in humans. Upon co-expression with 14-3-3epsilon, mutant channels still bound 14-3-3epsilon 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 14-3-3epsilon on C-terminally truncated HERG channels demonstrate the physiological importance of coupling beta-adrenergic stimulation and HERG channel activity.

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

M3 - SCORING: Zeitschriftenaufsatz

VL - 15

SP - 2888

EP - 2902

JO - HUM MOL GENET

JF - HUM MOL GENET

SN - 0964-6906

IS - 19

M1 - 19

ER -