Contents

📒 Onal 2014

Modeling CaMKII in cardiac physiology: from molecule to tissue

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INTRODUCTION

https://www.frontiersin.org/files/Articles/78809/fphar-05-00009-HTML/image_m/fphar-05-00009-g001.jpg

  • CaMKII regulates multiple important functions in neurons, including synthesis and release of neurotransmitters, modulation of ion channel activity, neurite extension, synaptic plasticity, learning, and gene expression
  • Abnormal CaMKII activity has been observed in human and animal models of cardiovascular disease (e.g., heart failure, myocardial infarction, arrhythmia)

MODELING THE CAMKII HOLOENZYME

  • CaMKIIα and CaMKIIβ expressed predominantly in neurons, whereas CaMKIIγ and CaMKIIδ are more uniformly expressed in other tissues
  • One of the most obvious and compelling challenges for modeling of CaMKII is autoregulation (autophophosphorylation). CaMKII autophophosphorylation is constrained by physical proximity of active subunits.
  • CaMKII activity is sensitive to changes in Ca2+ spike frequency and is capable of long-term storage of information
  • Also activated by oxidation

MODELING CAMKII SIGNALING IN THE INTACT CELL AND TISSUE

https://www.frontiersin.org/files/Articles/78809/fphar-05-00009-HTML/image_m/fphar-05-00009-g002.jpg

  • A: Hund-Rudy model. B: integrated CaMKII model, activated by self, Ca, and ROS
  • Sensitive to intracellular Ca2+, whose temporal and spatial profile is tightly controlled. any cell model of the kinase pathway must address the dynamic nature of the input, namely Ca2+-bound calmodulin.
  • Targets a large number of substrates in the cell (ion channels, signal transduction, gene expression) CaMKII-dependent effects on membrane ion channels and transporters important for Ca2+ cycling, including the ryanodine receptor (RyR), SERCA 2a (SR Ca2+ ATPase), phospholamban (PLB), and L-type Ca2+ channels.
  • Ability of CaMKII to regulate myocyte action potential, Ca2+ transient, and even contractile force in a rate-dependent manner
  • Roles for CaMKII in regulating AP heterogeneity and conduction, as well as cardiac pacemaking

MODELING CAMKII SIGNALING IN DISEASE

  • increased autophosphorylation and oxidation of the kinase results in increased activity that both increases Ca2+ leak from the sarcoplasmic reticulum and compromises availability of voltagegated Na+ channels (increased INaL) to create a favorable substrate for arrhythmias

FUTURE DIRECTIONS

  • future modeling efforts to address novel pathways for regulation of CaMKII activity (e.g., glycosylation)
  • understanding the “tipping point” from the adaptive to the maladaptive aspects of CaMKII signaling.

Reference


  1. Onal B, Unudurthi SD, Hund TJ. Modeling CaMKII in cardiac physiology: from molecule to tissue. Front. Pharmacol. 2014;5:9. doi:10.3389/fphar.2014.00009. PMC3912431 ↩︎