Analysis of the role of intracellular mechanisms for cardiac pacemaking by using conditional NCX1 and PKA mutants.

• Applicant: Dr. Stefan Herrmann, Ph.D.
• Subject Area: Pharmacology ; Anatomy and Physiology ; Cardiology, Angiology
• Term: from 2013 to 2017
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 239536961

The molecular mechanisms underlying the regular rhythmic activity of the cardiac pacemaker are not completely understood. It has been suggested that the interplay of various voltage-gated ion channels in the plasma membrane of sinoatrial cells is responsible for cardiac pacemaking. Recently, different groups challenged this view and postulated a new pacemaker concept based on intracellular calcium oscillations as the crucial mechanism underlying rhythmogenesis. However, this concept is controversial and will be investigated in the present research proposal. The cardiac sodium/calcium exchanger (NCX1) and the cAMP-dependent proteinkinase (PKA) represent central parts of this hypothesis. The influence of these proposed key players on the genesis, modulation and stability of the cardiac rhythm will be studied by the inducible inactivation of NCX1 and PKA in the cardiac conduction system of mice. For this purpose we generated an inducible Cre-transgene displaying a high selectivity for the cardiac pacemaking and conduction system. This line allows us to analyse the function of these genes on the cellular level in isolated sinoatrial node cells, on the tissue level in isolated heart preparations and also at the whole animal level. With the aid of these mutants we will be able to determine the true relevance of the proposed new pacemaker concept.

• DFG Programme: Research Grants