Voltage-dependent potassium channel regulators; novel perspectives for cardiac arrhythmias

• Applicant: Dr. Christine Alexandra Teutsch
• Subject Area: Cardiac and Vascular Surgery
• Term: from 2003 to 2007
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 5420937

Cardiac arrhythmias (CA) and sudden cardiac death (SCD) remain leading causes of death in developed countries. They result from rare congenital conditions as well as from damage to the heart and its conduction system by common cardiac diseases. There is growing evidence that the risk for the development of CA is increased by enhanced spatiotemporal dispersion of repolari-zation in the heart, which then alters its ability to sustain sinus rhythm. In the mammalian heart, voltage-gated potassium (K+)-currents are pivotal in shaping the waveform of the cardiac action potential (AP), particularly during repolarization. The importance of K+-currents in cardiac disease is evidenced by the identification of human mutations in pore-forming a-subunits of K+-channels in various known congenital arrhythmias, such as long QT-syndrome. However, the genetic ablation of KChIP2, a regulatory K+-channel b-subunit demonstrated the crucial role of K+-channel b-subunits in controlling the activity of the cardiac K+-channel. By inhi-biting the expression of early transient (Ito) K+-currents the ablation of KChIP2 has shown to provide substrate for malignant CA. The mechanisms regulating KChIP2 function have yet to be identified. While investigating cardiac conduction system enriched genes we identified KCR1, another K+-channel b-subunit. KCR1 is known to modulate a K+-current, which is a determinant of the neuronal AP. Based on the novel identification of KCR1 expression in cardiac conduction system cell lineages the role of KCR1 in the heart and its potential involvement in cardiac arrhythmias represents a very significant research opportunity. Improved understanding of the roles of the K+-channels b-subunits KChIP2 and KCR1, will lead to a better understanding of the mechanisms involved in the generation and modulation of cardiac K+-currents and could provide new insights into the molecular mechanisms responsible for CA and SCD.

• DFG Programme: Research Fellowships
• International Connection: USA
• Cooperation Partner: Professor Kenneth R. Chien, Ph.D.