title: Excitation-contraction coupling gain and cooperativity of the cardiac ryanodine receptor: a modeling approach.
abstract: During calcium-induced calcium-release, the ryanodine receptor (RyR) opens and releases large amounts of calcium from the sarcoplasmic reticulum 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, and hence, modulated by adrenergic stimulation through the phosphorylating action of protein kinase A. This has important implications for heart failure, where it has been hypothesized that RyR hyperphosphorylation, resulting in a loss of cooperativity, can lead to a persistent leak and a reduced sarcoplasmic-reticula 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 the binding of FK506 binding-protein, can have a dramatic effect on the excitation-contraction 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 heart-failure scenario.
authors.affiliation: Department of Physics and Center for Theoretical Biological Physics, University of California at San Diego, La Jolla, CA, USA.
authors.forename: Kai
authors.initials: K
authors.lastname: Wang
authors.forename: Yuhai
authors.initials: Y
authors.lastname: Tu
authors.forename: Wouter-Jan
authors.initials: WJ
authors.lastname: Rappel
authors.forename: Herbert
authors.initials: H
authors.lastname: Levine
mesh_terms: D000495:Allosteric Site; D000818:Animals; D001703:Biophysics / Q000379:methods*; D002118:Calcium / Q000737:chemistry; D015220:Calcium Channels / Q000737:chemistry; D017868:Cyclic AMP-Dependent Protein Kinases / Q000737:chemistry; D004594:Electrophysiology; D006331:Heart Diseases / Q000378:metabolism; D006801:Humans; D051379:Mice; D008956:Models, Chemical; D008958:Models, Molecular; D015233:Models, Statistical; D032342:Muscle Cells / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism*; D010766:Phosphorylation; D011817:Rabbits; D051381:Rats; D019837:Ryanodine Receptor Calcium Release Channel / Q000737:chemistry*; D012519:Sarcoplasmic Reticulum / Q000378:metabolism; D022021:Tacrolimus Binding Proteins / Q000737:chemistry; D013816:Thermodynamics; D013997:Time Factors
chemical_list: D015220:Calcium Channels; D019837:Ryanodine Receptor Calcium Release Channel; D017868:Cyclic AMP-Dependent Protein Kinases; D022021:Tacrolimus Binding Proteins; D002118:Calcium