title: A human ventricular myocyte model with a refined representation of excitation-contraction coupling.
abstract: Cardiac Ca(2+)-induced Ca(2+) release (CICR) occurs by a regenerative activation of ryanodine receptors (RyRs) within each Ca(2+)-releasing unit, triggered by the activation of L-type Ca(2+) channels (LCCs). CICR is then terminated, most probably by depletion of Ca(2+) in the junctional sarcoplasmic reticulum (SR). Hinch et al. previously developed a tightly coupled LCC-RyR mathematical model, known as the Hinch model, that enables simulations to deal with a variety of functional states of whole-cell populations of a Ca(2+)-releasing unit using a personal computer. In this study, we developed a membrane excitation-contraction model of the human ventricular myocyte, which we call the human ventricular cell (HuVEC) model. This model is a hybrid of the most recent HuVEC models and the Hinch model. We modified the Hinch model to reproduce the regenerative activation and termination of CICR. In particular, we removed the inactivated RyR state and separated the single step of RyR activation by LCCs into triggering and regenerative steps. More importantly, we included the experimental measurement of a transient rise in Ca(2+) concentrations ([Ca(2+)], 10-15 μM) during CICR in the vicinity of Ca(2+)-releasing sites, and thereby calculated the effects of the local Ca(2+) gradient on CICR as well as membrane excitation. This HuVEC model successfully reconstructed both membrane excitation and key properties of CICR. The time course of CICR evoked by an action potential was accounted for by autonomous changes in an instantaneous equilibrium open probability of couplons. This autonomous time course was driven by a core feedback loop including the pivotal local [Ca(2+)], influenced by a time-dependent decay in the SR Ca(2+) content during CICR.
authors.affiliation: Biosimulation Research Center, College of Life Sciences, Ritsumeikan University, Shiga, Japan.
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Himeno
authors.affiliation: Biosimulation Research Center, College of Life Sciences, Ritsumeikan University, Shiga, Japan; Nippon Shinyaku Co., Ltd., Kyoto, Japan.
authors.forename: Keiichi
authors.initials: K
authors.lastname: Asakura
authors.affiliation: Biosimulation Research Center, College of Life Sciences, Ritsumeikan University, Shiga, Japan; Oxford Centre for Diabetes Endocrinology and Metabolism, University of Oxford, Oxford, UK.
authors.forename: Chae Young
authors.initials: CY
authors.lastname: Cha
authors.affiliation: Biosimulation Research Center, College of Life Sciences, Ritsumeikan University, Shiga, Japan.
authors.forename: Hiraku
authors.initials: H
authors.lastname: Memida
authors.affiliation: Department of Pharmacology, University of Oxford, Oxford, UK.
authors.forename: Trevor
authors.initials: T
authors.lastname: Powell
authors.affiliation: Biosimulation Research Center, College of Life Sciences, Ritsumeikan University, Shiga, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Amano
authors.affiliation: Biosimulation Research Center, College of Life Sciences, Ritsumeikan University, Shiga, Japan. Electronic address: noma@sk.ritsumei.ac.jp.
authors.forename: Akinori
authors.initials: A
authors.lastname: Noma
mesh_terms: D002118:Calcium / Q000378:metabolism; D020746:Calcium Channels, L-Type / Q000378:metabolism; D002413:Cations, Divalent / Q000378:metabolism; D002462:Cell Membrane / Q000502:physiology; D056966:Excitation Contraction Coupling / Q000502:physiology*; D025461:Feedback, Physiological; D006352:Heart Ventricles / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D008955:Models, Cardiovascular; D032342:Muscle Cells / Q000502:physiology*; D018408:Patch-Clamp Techniques; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism; D012519:Sarcoplasmic Reticulum / Q000378:metabolism
chemical_list: D020746:Calcium Channels, L-Type; D002413:Cations, Divalent; D019837:Ryanodine Receptor Calcium Release Channel; D002118:Calcium