title: Mechanisms of excitation-contraction coupling in an integrative model of the cardiac ventricular myocyte.
abstract: It is now well established that characteristic properties of excitation-contraction (EC) coupling in cardiac myocytes, such as high gain and graded Ca(2+) release, arise from the interactions that occur between L-type Ca(2+) channels (LCCs) and nearby ryanodine-sensitive Ca(2+) release channels (RyRs) in localized microdomains. Descriptions of Ca(2+)-induced Ca(2+) release (CICR) that account for these local mechanisms are lacking from many previous models of the cardiac action potential, and those that do include local control of CICR are able to reconstruct properties of EC coupling, but require computationally demanding stochastic simulations of approximately 10(5) individual ion channels. In this study, we generalize a recently developed analytical approach for deriving simplified mechanistic models of CICR to formulate an integrative model of the canine cardiac myocyte which is computationally efficient. The resulting model faithfully reproduces experimentally measured properties of EC coupling and whole cell phenomena. The model is used to study the role of local redundancy in L-type Ca(2+) channel gating and the role of dyad configuration on EC coupling. Simulations suggest that the characteristic steep rise in EC coupling gain observed at hyperpolarized potentials is a result of increased functional coupling between LCCs and RyRs. We also demonstrate mechanisms by which alterations in the early repolarization phase of the action potential, resulting from reduction of the transient outward potassium current, alters properties of EC coupling.
authors.affiliation: The Center for Cardiovascular Bioinformatics and Modeling and The Whitaker Biomedical Engineering Institute, The Johns Hopkins University Whiting School of Engineering and School of Medicine, Baltimore, Maryland, USA. jgreenst@jhu.edu
authors.forename: Joseph L
authors.initials: JL
authors.lastname: Greenstein
authors.forename: Robert
authors.initials: R
authors.lastname: Hinch
authors.forename: Raimond L
authors.initials: RL
authors.lastname: Winslow
mesh_terms: D000200:Action Potentials; D000818:Animals; D001703:Biophysics / Q000379:methods*; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000737:chemistry; D020746:Calcium Channels, L-Type / Q000737:chemistry; D020013:Calcium Signaling; D002462:Cell Membrane / Q000378:metabolism; D003198:Computer Simulation; D004285:Dogs; D006352:Heart Ventricles / Q000378:metabolism*; D015640:Ion Channel Gating; D008390:Markov Chains; D008564:Membrane Potentials; D008954:Models, Biological; D008955:Models, Cardiovascular; D032342:Muscle Cells / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D012433:Ryanodine / Q000378:metabolism; D019837:Ryanodine Receptor Calcium Release Channel / Q000737:chemistry*; D012519:Sarcoplasmic Reticulum / Q000378:metabolism; D013997:Time Factors
chemical_list: D015220:Calcium Channels; D020746:Calcium Channels, L-Type; D019837:Ryanodine Receptor Calcium Release Channel; D012433:Ryanodine; D002118:Calcium