BIOPHYSICAL THEORY AND MODELING |
Excitation-contraction coupling gain and cooperativity of the cardiac ryanodine receptor: a modeling approach
Kai Wang 1, Yuhai Tu 2, Wouter-Jan Rappel 1 and Herbert Levine 3*
1 UC San Diego
2 IBM T. J. Watson Research Center
3 Univ. California, San Diego
* To whom correspondence should be addressed. E-mail: hlevine{at}ucsd.edu.
Submitted on January 10, 2005
Revised on February 23, 2005
Accepted on 5 August 2005
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Abstract |
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During calcium-induced-calcium-release, the ryanodine receptor (RyR) opens and releases large amounts of calcium from the sarcoplasmic reticulum (SR) into the cytoplasm of the myocyte. Recent experiments have suggested that cooperativity between the four monomers comprising the RyR plays an important role in the dynamics of the overall receptor. Furthermore, this cooperativity can be affected by the binding of FK506 binding protein (FKBP) and hence modulated by adrenergic stimulation through the phosphorylating action of PKA. This has important implications for heart failure (HF), where it has been hypothesized that RyR hyperphosphorylation, resulting in a loss of cooperativity, can lead to a persistent leak and a reduced SR content. In this study, we construct a theoretical model that examines the cooperativity via the assumption of an allosteric interaction between the four subunits. We find that the level of cooperativity, regulated by FKBP binding, can have a dramatic effect on the excitation-contraction (E-C) coupling gain and that this gain exhibits a clear maximum. These findings are compared to currently available data from different species and allows for an evaluation of the aforementioned HF scenario.
Key Words:
FKBP, cooperativity, excitation-contraction coupling gain
