Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.17 (CaMKII)
 4,029 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

During heart failure, the ability of the sarcoplasmic reticulum (SR) to store Ca(2+) is severely impaired resulting in abnormal Ca(2+) cycling and excitation-contraction (EC) coupling. Recently, it has been proposed that "leaky" ryanodine receptors (RyRs) contribute to diminished Ca(2+) levels in the SR. Various groups have experimentally investigated the effects of RyR phosphorylation mediated by Ca(2+)/calmodulin-dependent kinase II (CaMKII) on RyR behavior. Some of these results are difficult to interpret since RyR gating is modulated by many external proteins and ions, including Ca(2+). Here, we present a mathematical model representing CaMKII-RyR interaction in the canine ventricular myocyte. This is an extension of our previous model which characterized CaMKII phosphorylation of L-type Ca(2+) channels (LCCs) in the cardiac dyad. In this model, it is assumed that upon phosphorylation, RyR Ca(2+)-sensitivity is increased. Individual RyR phosphorylation is modeled as a function of dyadic CaMKII activity, which is modulated by local Ca(2+) levels. The model is constrained by experimental measurements of Ca(2+) spark frequency and steady state RyR phosphorylation. It replicates steady state RyR (leak) fluxes in the range measured in experiments without the addition of a separate passive leak pathway. Simulation results suggest that under physiological conditions, CaMKII phosphorylation of LCCs ultimately has a greater effect on RyR flux as compared with RyR phosphorylation. We also show that phosphorylation of LCCs decreases EC coupling gain significantly and increases action potential duration. These results suggest that LCC phosphorylation sites may be a more effective target than RyR sites in modulating diastolic RyR flux.
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PMID:Role of CaMKII in RyR leak, EC coupling and action potential duration: a computational model. 2065 25

Excitation-contraction coupling (ECC) in the cardiac myocyte is mediated by a number of highly integrated mechanisms of intracellular Ca(2+) transport. Voltage- and Ca(2+)-dependent L-type Ca(2+) channels (LCCs) allow for Ca(2+) entry into the myocyte, which then binds to nearby ryanodine receptors (RyRs) and triggers Ca(2+) release from the sarcoplasmic reticulum in a process known as Ca(2+)-induced Ca(2+) release. The highly coordinated Ca(2+)-mediated interaction between LCCs and RyRs is further regulated by the cardiac isoform of the Ca(2+)/calmodulin-dependent protein kinase (CaMKII). Because CaMKII targets and modulates the function of many ECC proteins, elucidation of its role in ECC and integrative cellular function is challenging and much insight has been gained through the use of detailed computational models. Multiscale models that can both reconstruct the detailed nature of local signaling events within the cardiac dyad and predict their functional consequences at the level of the whole cell have played an important role in advancing our understanding of CaMKII function in ECC. Here, we review experimentally based models of CaMKII function with a focus on LCC and RyR regulation, and the mechanistic insights that have been gained through their application.
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PMID:Modeling CaMKII-mediated regulation of L-type Ca(2+) channels and ryanodine receptors in the heart. 2477 82