title: Simulation of the effects of moderate stimulation/inhibition of the β1-adrenergic signaling system and its components in mouse ventricular myocytes.
abstract: The β1-adrenergic signaling system is one of the most important protein signaling systems in cardiac cells. It regulates cardiac action potential duration, intracellular Ca(2+) concentration ([Ca(2+)]i) transients, and contraction force. In this paper, a comprehensive experimentally based mathematical model of the β1-adrenergic signaling system for mouse ventricular myocytes is explored to simulate the effects of moderate stimulations of β1-adrenergic receptors (β1-ARs) on the action potential, Ca(2+) and Na(+) dynamics, as well as the effects of inhibition of protein kinase A (PKA) and phosphodiesterase of type 4 (PDE4). Simulation results show that the action potential prolongations reach saturating values at relatively small concentrations of isoproterenol (∼0.01 μM), while the [Ca(2+)]i transient amplitude saturates at significantly larger concentrations (∼0.1-1.0 μM). The differences in the response of Ca(2+) and Na(+) fluxes to moderate stimulation of β1-ARs are also observed. Sensitivity analysis of the mathematical model is performed and the model limitations are discussed. The investigated model reproduces most of the experimentally observed effects of moderate stimulation of β1-ARs, PKA, and PDE4 inhibition on the L-type Ca(2+) current, [Ca(2+)]i transients, and the sarcoplasmic reticulum Ca(2+) load and makes testable predictions for the action potential duration and [Ca(2+)]i transients as functions of isoproterenol concentration.
authors.affiliation: Department of Mathematics and Statistics, Georgia State University, Atlanta, Georgia; and.
authors.forename: Mark
authors.initials: M
authors.lastname: Grinshpon
authors.affiliation: Department of Mathematics and Statistics, Georgia State University, Atlanta, Georgia; and Neuroscience Institute, Georgia State University, Atlanta, Georgia vbondarenko@gsu.edu.
authors.forename: Vladimir E
authors.initials: VE
authors.lastname: Bondarenko
mesh_terms: D000200:Action Potentials; D058665:Adrenergic beta-1 Receptor Agonists / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism; D020746:Calcium Channels, L-Type / Q000187:drug effects / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects; D003198:Computer Simulation; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4 / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006352:Heart Ventricles / Q000187:drug effects* / Q000378:metabolism; D007545:Isoproterenol / Q000494:pharmacology*; D007700:Kinetics; D008954:Models, Biological; D008955:Models, Cardiovascular; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism; D058988:Phosphodiesterase 4 Inhibitors / Q000494:pharmacology; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D018342:Receptors, Adrenergic, beta-1 / Q000187:drug effects* / Q000378:metabolism; D012519:Sarcoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D012964:Sodium / Q000378:metabolism
chemical_list: C547788:Adrb1 protein, mouse; D058665:Adrenergic beta-1 Receptor Agonists; D020746:Calcium Channels, L-Type; D058988:Phosphodiesterase 4 Inhibitors; D047428:Protein Kinase Inhibitors; D018342:Receptors, Adrenergic, beta-1; D012964:Sodium; D017868:Cyclic AMP-Dependent Protein Kinases; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D007545:Isoproterenol; D002118:Calcium
keywords: Ca2+ dynamics; Na+ dynamics; cardiac action potential; phosphodiesterase of type 4; protein kinase A