Medical and health sciences
- Cardiac and vascular medicine not elsewhere classified
- Cell physiology
- Organ physiology
Connexins are crucial proteins in the heart that facilitate impulse conduction over the cardiac tissue thereby coordinating the atrioventricular contraction cycle in a spatiotemporal manner. Connexins form hemichannels that assemble as gap junctions and directly connect cardiomyocytes as well as cells of specialized conduction tissues. Hemichannels not only combine to form gap junctions but are also present as free membrane channels not being part of gap junctions. We and others recently found these are involved in disturbances of the cardiac rhythm, especially by triggered action potential generation. Here, we will investigate activation mechanisms leading to hemichannel opening and how this disturbs heart rhythm in cardiac hypertrophy and failure. Our first aim is to elucidate the role of inositol-trisphosphate (IP3)/calcium-signaling as a trigger for hemichannel opening in ventricular cardiomyocytes and how this relates to calcium-induced calcium release via ryanodine receptors. The second aim is to investigate the effect of SARS-Cov-2 related pro-inflammatory cytokines, which also impact IP3/calcium-signaling, on hemichannel opening and subsequent arrhythmic consequences, to improve our understanding of malignant ventricular arrhythmogenicity in Covid-19 patients. In this context, we further scrutinize whether hemichannel leakage current slows down impulse conduction and thereby acts through an arrhythmogenic mechanism distinct from triggered action potential generation.