Interaktion von HERG und KVLQT1: Aufklärung der Interaktionsstelle, der molekularen Interaktionsmechanismen sowie der Rolle bei humanem long-QT Syndrom

• Antragsteller: Professor Dr. Joachim R. Ehrlich
• Fachliche Zuordnung: Kardiologie, Angiologie
• Förderung: Förderung von 2005 bis 2008
• Projektkennung: Deutsche Forschungsgemeinschaft (DFG) - Projektnummer 5447691

Long QT syndrome (LQTS) is a disease often caused by mutations in ion channel genes and affected patients are at risk for sudden cardiac death. Mutations in the KCNH2 gene result in LQTS 2 and mutations in KCNQ1 underlie LQTS 1. We had originally demonstrated a direct protein-protein interaction between these respective ion channels. In the previous funding period we successfully extended these findings and identified a chaperone effect of KCNQ1 to KCNH2 trafficking with potential physiological relevance. We performed detailed electrophysiological and pharmacological studies excluding hetero-tetramerization of KCNH2 and KCNQ1 α-subunits. Dedicated protein biochemical studies using co-immunoprecipitations, GST-fusion protein pulldown and blot overlay assays indicated an importance of the KCNH2 n-terminus in the interaction. Immunoblots indicated increased KCNH2 expression at the plasma membrane compatible with increased membrane translocation that was confirmed by confocal imaging. Use of a trafficking deficient KCNQ1 (T587M) mutation (described in a family with clinically severe LQTS) reduced KCNH2 membrane translocation and suggested a physiologically relevant contribution of this newly described chaperone mechanism to LQTS phenotype severity. Now we apply for an extension of the funding period to provide evidence for a role of this interaction between T587M and KCNH2 for trafficking in human cardiac cells.

• DFG-Verfahren: Sachbeihilfen