title: Modeling beta-adrenergic control of cardiac myocyte contractility in silico.
abstract: The beta-adrenergic signaling pathway regulates cardiac myocyte contractility through a combination of feedforward and feedback mechanisms. We used systems analysis to investigate how the components and topology of this signaling network permit neurohormonal control of excitation-contraction coupling in the rat ventricular myocyte. A kinetic model integrating beta-adrenergic signaling with excitation-contraction coupling was formulated, and each subsystem was validated with independent biochemical and physiological measurements. Model analysis was used to investigate quantitatively the effects of specific molecular perturbations. 3-Fold overexpression of adenylyl cyclase in the model allowed an 85% higher rate of cyclic AMP synthesis than an equivalent overexpression of beta 1-adrenergic receptor, and manipulating the affinity of Gs alpha for adenylyl cyclase was a more potent regulator of cyclic AMP production. The model predicted that less than 40% of adenylyl cyclase molecules may be stimulated under maximal receptor activation, and an experimental protocol is suggested for validating this prediction. The model also predicted that the endogenous heat-stable protein kinase inhibitor may enhance basal cyclic AMP buffering by 68% and increasing the apparent Hill coefficient of protein kinase A activation from 1.0 to 2.0. Finally, phosphorylation of the L-type calcium channel and phospholamban were found sufficient to predict the dominant changes in myocyte contractility, including a 2.6x increase in systolic calcium (inotropy) and a 28% decrease in calcium half-relaxation time (lusitropy). By performing systems analysis, the consequences of molecular perturbations in the beta-adrenergic signaling network may be understood within the context of integrative cellular physiology.
authors.affiliation: Department of Bioengineering, University of California, San Diego, La Jolla, California 92093-0412, USA.
authors.forename: Jeffrey J
authors.initials: JJ
authors.lastname: Saucerman
authors.forename: Laurence L
authors.initials: LL
authors.lastname: Brunton
authors.forename: Anushka P
authors.initials: AP
authors.lastname: Michailova
authors.forename: Andrew D
authors.initials: AD
authors.lastname: McCulloch
mesh_terms: D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D020746:Calcium Channels, L-Type / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000378:metabolism; D002772:Cholera Toxin / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D006801:Humans; D007545:Isoproterenol / Q000494:pharmacology; D007700:Kinetics; D008390:Markov Chains; D008954:Models, Biological; D008956:Models, Chemical; D008962:Models, Theoretical; D009206:Myocardium / Q000166:cytology* / Q000378:metabolism; D010766:Phosphorylation; D011493:Protein Kinase C / Q000378:metabolism; D011943:Receptors, Adrenergic, beta / Q000378:metabolism*; D015398:Signal Transduction; D013597:Systems Analysis; D013997:Time Factors; D000099211:Phospholamban
chemical_list: D000262:Adenylyl Cyclases; D020746:Calcium Channels, L-Type; D002135:Calcium-Binding Proteins; D002772:Cholera Toxin; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D007545:Isoproterenol; D011493:Protein Kinase C; D011943:Receptors, Adrenergic, beta; D000099211:Phospholamban