Role of CaMKII in RyR leak, EC coupling and action potential duration: a computational model.

Journal of Molecular and Cellular Cardiology
Yasmin L HashambhoyRaimond L Winslow

Abstract

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 measu...Continue Reading

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Citations

May 27, 2011·European Journal of Applied Physiology·Guri KaurstadUlrik Wisløff
Jun 9, 2012·Circulation Research·Paari Dominic SwaminathanMark E Anderson
Mar 9, 2013·Advances in Physiology Education·Jose L PuglisiDonald M Bers
Feb 2, 2016·Journal of Molecular and Cellular Cardiology·Andrew P WescottGeorge S B Williams
Nov 13, 2015·Wiley Interdisciplinary Reviews. Systems Biology and Medicine·Raimond L WinslowJoseph L Greenstein
Oct 18, 2015·Journal of Molecular and Cellular Cardiology·Juan F GomezBeatriz Trenor
Dec 18, 2014·Biophysical Journal·Mark A WalkerRaimond L Winslow
Sep 25, 2010·Wiley Interdisciplinary Reviews. Systems Biology and Medicine·Raimond L WinslowJoseph L Greenstein
Aug 20, 2015·Biophysical Journal·Panagiota T FoteinouRaimond L Winslow
Apr 30, 2013·Journal of Molecular and Cellular Cardiology·Elena C LascanoJorge A Negroni
Jul 2, 2011·Progress in Biophysics and Molecular Biology·Raimond L Winslow, Joseph L Greenstein
Nov 8, 2011·Journal of Molecular and Cellular Cardiology·Ona Z LiuEric A Sobie
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