Departmental Seminar Series: Donald Bers (Professor and Chair, Department of Pharmacology, School of Medicine, UC Davis)
Cardiac CaMKII signaling in heart failure, arrhythmias and transcriptional regulation: Imaging and Modeling
CaMKII regulates many processes in cardiac myocytes. We used FRET-based sensors to measure dynamic beat-to-beat changes in [Ca-CaM] in intact myocytes and mathematical models of CaMKII activation in different cellular domains. CaMKII has acute effects on numerous cardiac ion channels (e.g. Ca, Na, K and ryanodine receptor, RyR causing Ca sparks & waves) and CaMKII expression and activity is enhanced in heart failure (HF). How do CaMKII effects integrate at the myocyte level to influence cardiac action potential (AP) and arrhythmias? CaMKII-dependent effects on Na current phenocopy a human mutation that causes combined long-QT and Brugada syndromes in patients. CaMKII also mediates Ca current facilitation, and other ion channel effects than can be arrhythmogenic. CaM, calcineurin and CaMKII are also involved in nuclear transcriptional regulation in pathways that involve histone deacetylases (HDAC) and NFAT, and these may contribute to the development of cardiac hypertrophy, failure and arrhythmias. HDAC5 binds to MEF2 and suppresses MEF2-driven transcription, whereas HDAC5 nuclear export relieves this and thereby activates hypertrophic gene transcription. Remarkably, this Ca-dependent pathway is insensitive to global Ca transients at each heartbeat, and is functionally insulated from Ca involved in EC coupling. Thus myocytes can distinguish simultaneous local and global Ca signals involved in contractile activation from those targeting gene expression. Thus Ca and CaMKII signaling in cardiac myocytes can mediate many acute effects (in seconds to hours) that influence cardiac electrophysiology and contractile function, and also on a longer time scale (tens of minutes to days) to influence gene expression and contribute to cellular and molecular remodeling.
When: Thursday, April 5, 2012 4:10 PM
Where: 1005 GBSF