Molecular analysis of the regulation of cardiac IK1 current by protein kinase A and protein kinase C

• Applicant: Dr. Edgar Zitron
• Subject Area: Cardiology, Angiology
• Term: from 2008 to 2013
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 74524368

The cardiac inwardly rectifying potassium current IKI is essential to maintain the resting membrane potential (RMP) of cardiomyocytes. Inhibition of IKI current disturbs the stability of RMP and facilitates irregular depolarisations which may trigger ventricular tachycardias. It has been demonstrated that pathophysiologically relevant neurohumoral pathways (a-i adrenoreceptors, ßv2 adrenoreceptors, ETA endothelin receptors) inhibit IKI current involving protein kinase A (PKA) and protein kinase C (PKC) dependent signalling, thereby favouring arrhythmogenesis.On the molecular level, cardiac IKI current is mediated by three different channel subunits (Kir2.1, Kir2.2 and Kir2.3) that co-assemble to form heterotetrameric channels. We and others have provided evidence that these channel subunits are differentially regulated by PKA and PKC, and that targeting of signalling enzymes to the channels is mediated by A Kinase Anchoring Proteins (AKAPs). However, the precise molecular mechanisms of this regulation are unknown.The specific aims of this project are to elucidate the molecular mechanisms underlying the regulation of IKI current by protein kinases A and C and to define the role of AKAPs in this regulation. The modulation of IKI current by PKA and PKC will be analysed with molecular and cellular electrophysiology to identify the involved enzyme isoforms and the phosphorylation sites within the channel subunits. An integrative approach including electrophysiology, imaging, proteomics and biochemistry will be applied to define the role of specific AKAPs for these regulations and to identify binding domains between the AKAP and the corresponding channel subunit.

• DFG Programme: Research Grants
• Participating Persons: Professor Dr. Christoph Cremer; Dr. Christoph Karle