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Projekt Druckansicht

Arrhythmogenesis associated with mutations in KCNH2 (HERG)

Antragsteller Professor Dr. Olaf Pongs
Fachliche Zuordnung Public Health, Gesundheitsbezogene Versorgungsforschung, Sozial- und Arbeitsmedizin
Förderung Förderung von 2005 bis 2008
Projektkennung Deutsche Forschungsgemeinschaft (DFG) - Projektnummer 5440778
 
Erstellungsjahr 2008

Zusammenfassung der Projektergebnisse

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 14-3-3c. 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 14-3-3E. When expressed in CHO cells, the mutants produced fimctional HERG channels with normal kinetic properties. We now provide evidence that HERG channel regulation by 14-3-3e is of physiological significance in humans. Upon co-expression with 14-3-3E, mutant channels still bound 14-3- 3E but did not respond with a hyperpolarizing shift in voltage dependence as seen in wildtype 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 14-3-3E on C-terminally truncated HERG channels demonstrate the physiological importance of coupling ß-adrenergic stimulation and HERG channel activity.

Projektbezogene Publikationen (Auswahl)

  • Choe CU (2008) "Elektrophysiologische, proteinbiochemische und immunzytochemische Charakterisierung C-terminaler HERG (LQT2) Mutationen"

  • Choe CU, Schulze-Bahr E, Neu A, Xu J, Zhu ZI, Sauter K, Bahnng R, Prion S, Guicheney P, Monmg G, Neapohtano C, Heidemann J, Clancy CE, Pongs 0, and Isbrandt D C-terminal HERG (LQT2) mutations disrupt IKr channel regulation through 14-3-3epsilon Hum Mol Genet \S 2888-2902,2006

 
 

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