Role of CaMKII and PKA in Early Afterdepolarization of Human Ventricular Myocardium Cell: A Computational Model Study

Comput Math Methods Med. 2016:2016:4576313. doi: 10.1155/2016/4576313. Epub 2016 Dec 8.

Abstract

Early afterdepolarization (EAD) plays an important role in arrhythmogenesis. Many experimental studies have reported that Ca2+/calmodulin-dependent protein kinase II (CaMKII) and β-adrenergic signaling pathway are two important regulators. In this study, we developed a modified computational model of human ventricular myocyte to investigate the combined role of CaMKII and β-adrenergic signaling pathway on the occurrence of EADs. Our simulation results showed that (1) CaMKII overexpression facilitates EADs through the prolongation of late sodium current's (INaL) deactivation progress; (2) the combined effect of CaMKII overexpression and activation of β-adrenergic signaling pathway further increases the risk of EADs, where EADs could occur at shorter cycle length (2000 ms versus 4000 ms) and lower rapid delayed rectifier K+ current (IKr) blockage (77% versus 85%). In summary, this study computationally demonstrated the combined role of CaMKII and β-adrenergic signaling pathway on the occurrence of EADs, which could be useful for searching for therapy strategies to treat EADs related arrhythmogenesis.

MeSH terms

  • Action Potentials / physiology
  • Animals
  • Arrhythmias, Cardiac
  • Binding Sites
  • Calcium / metabolism
  • Calcium Signaling / physiology
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2 / metabolism*
  • Computer Simulation
  • Cyclic AMP-Dependent Protein Kinases / metabolism*
  • Dogs
  • Heart Ventricles / pathology
  • Humans
  • Models, Cardiovascular
  • Myocardium / pathology*
  • Myocytes, Cardiac / cytology
  • Potassium Channels / metabolism
  • Receptors, Adrenergic, beta / metabolism*
  • Signal Transduction

Substances

  • Potassium Channels
  • Receptors, Adrenergic, beta
  • Cyclic AMP-Dependent Protein Kinases
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2
  • Calcium