Synergy between CaMKII substrates and β-adrenergic signaling in regulation of cardiac myocyte Ca(2+) handling

Biophys J. 2010 Oct 6;99(7):2038-47. doi: 10.1016/j.bpj.2010.08.016.

Abstract

Cardiac excitation-contraction coupling is a highly coordinated process that is controlled by protein kinase signaling pathways, including Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) and protein kinase A (PKA). Increased CaMKII expression and activity (as occurs during heart failure) destabilizes EC coupling and may lead to sudden cardiac death. To better understand mechanisms of cardiac CaMKII function, we integrated dynamic CaMKII-dependent regulation of key Ca(2+) handling targets with previously validated models of cardiac EC coupling, Ca(2+)/calmodulin-dependent activation of CaMKII, and β-adrenergic activation of PKA. Model predictions are validated against CaMKII-overexpression data from rabbit ventricular myocytes. The model demonstrates how overall changes to Ca(2+) handling during CaMKII overexpression are explained by interactions between individual CaMKII substrates. CaMKII and PKA activities during β-adrenergic stimulation may synergistically facilitate inotropic responses and contribute to a CaMKII-Ca(2+)-CaMKII feedback loop. CaMKII regulated early frequency-dependent acceleration of relaxation and EC coupling gain (which was highly sarcoplasmic reticulum Ca(2+) load-dependent). Additionally, the model identifies CaMKII-dependent ryanodine receptor hyperphosphorylation as a proarrhythmogenic trigger. In summary, we developed a detailed computational model of CaMKII and PKA signaling in cardiac myocytes that provides unique insights into their regulation of normal and pathological Ca(2+) handling.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Arrhythmias, Cardiac / enzymology
  • Arrhythmias, Cardiac / physiopathology
  • Calcium / metabolism
  • Calcium Channels, L-Type / metabolism
  • Calcium Signaling*
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2 / metabolism*
  • Electrophysiological Phenomena
  • Excitation Contraction Coupling
  • Feedback, Physiological
  • Models, Biological
  • Myocardial Contraction
  • Myocytes, Cardiac / enzymology*
  • Myocytes, Cardiac / pathology
  • Phosphorylation
  • Protein Binding
  • Rabbits
  • Receptors, Adrenergic, beta / metabolism*
  • Substrate Specificity
  • Time Factors

Substances

  • Calcium Channels, L-Type
  • Receptors, Adrenergic, beta
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2
  • Calcium