📒 Onal 2014
Modeling CaMKII in cardiac physiology: from molecule to tissue
- 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
- 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 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.