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Simulation of Ca-Calmodulin Dependent Protein Kinase II (CaMKII)

Simulation of Ca-Calmodulin Dependent Protein Kinase II (CaMKII) on Rabbit Ventricular Ion Currents and Action Potentials. E Grandi*, JL Puglisi*, S Wagner # , LS Maier # , S Severi § and DM Bers*. * Department of Physiology, Loyola University Chicago, IL, USA

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Simulation of Ca-Calmodulin Dependent Protein Kinase II (CaMKII)

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  1. Simulation of Ca-Calmodulin Dependent Protein Kinase II (CaMKII) on Rabbit Ventricular Ion Currents and Action Potentials E Grandi*, JL Puglisi*, S Wagner#, LS Maier#, S Severi§ and DM Bers* * Department of Physiology, Loyola University Chicago, IL, USA # Department of Cardiology & Pneumology, Georg-August-University Göttingen, Germany §Biomedical Engineering Laboratory, DEIS, University of Bologna, Italy Stefano Morotti smorotti@gmail.com 31 Luglio 2009 C3MIG

  2. CaMKII Ca2+/calmodulin dependent protein kinase II serine/threonine-specific protein kinase primarily regulated by the Ca2+/calmodulin complex Calmodulin (CaM) CALcium MODULated proteIN C3MIG

  3. CaMKII Targets in the Heart cytosolic δ isoform Wagner et al., 2006b Wagner et al., 2006a Kohlhaas et al., 2006 Phospholamban -> SERCA (Sarco/Endoplasmic Reticulum Ca2+-ATPase) Ryanodine Receptors -> CICR (Calcium Induced - Calcium Relaese) C3MIG

  4. Ion Currents and Action Potential Sodium (inward) current (INa) L-type Calcium (inward) current (ICaL) Potassium (outward) transient current (Ito1) C3MIG

  5. Na+ Channelopaties Inherited Diseases Long QT Syndrome (LQT3) Brugada Syndrome Conduction Disease Overlap Syndromes (1795insD in SCN5A) Acquired Diseases Drug-indiced LQTS Ischemia Heart Failure (over-expression of CaMKII) C3MIG

  6. Na+ Channelopaties shifted availability slowed recovery increased intermediate inactivation persistent current Loss of function faster heart rates -> Brugada Gain of function slower heart rates -> LQT INa C3MIG

  7. 4. Cardiac AP 2. Markovian model of current 5. Arrhythmia 3. AP model Mathematical Modeling 1. Functional Analysis of INa Na+ channel model Modified from Clancy et al., 2002 Rabbit Ventricular AP Model Modified from Shannon et al., 2004 Matlab and Simulink were used for all numerical computations C3MIG

  8. INa Simulation Steady-stateinactivation Steady-stateactivation Intermediate inactivation Recoveryfrominactivation Experiments from Wagner et al., 2006 - Rabbit myocytes overexpressing CaMKII C3MIG

  9. INa Simulation Experimental Simulated Fast inactivation Late current Experiments from Wagner et al., 2006 - Rabbit myocytes overexpressing CaMKII C3MIG

  10. CaMKII-dependent INa alterations on AP Simulated C3MIG

  11. Experimental Simulated CaMKII-dependent INa alterations on [Na+]i Experiments from Wagner et al., 2006 - Rabbit myocytes overexpressing CaMKII C3MIG

  12. ICaL Simulation Exp Sim Experiments from Kohlhaas et al., 2006 - Rabbit myocytes overexpressing CaMKII C3MIG

  13. Experimental Simulated Ito,total Ito,slow Ito,fast Ito Simulation Recoveryfrominactivation Experiments from Wagner et al., 2006 - Rabbit myocytes overexpressing CaMKII C3MIG

  14. 37ºC, physiological conditions Exp Sim [1 Hz] CaMKII-dependent INa, ICaL and Ito alterations on AP Simulated [1 Hz] Experiments from Wagner et al., 2006 - Rabbit myocytes overexpressing CaMKII C3MIG

  15. APD Sensitivity to Late INa C3MIG

  16. HF Ito Heterogeneity / Down-regulation Simulated C3MIG

  17. Conclusions • There are several potential pathways by which CaMKII may be arrhythmogenic: • CaMKII effects on INa, ICaL and Ito combined with transmural heterogeneity of Ito and Ito down-regulation in HF may accentuate dispersion of repolarization and predispose to reentrant arrhythmias. • The in silico analysis provides a useful framework to consider pathways by which CaMKII may contribute to arrhythmogenesis and highlight novel potential therapeutic targets. C3MIG

  18. Grazie per l’attenzione! C3MIG

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