%0 Journal Article %1 Sauc_2003_47997 %A Saucerman, Jeffrey J %A Brunton, Laurence L %A Michailova, Anushka P %A McCulloch, Andrew D %D 2003 %J J Biol Chem %K AMP, AMP-Dependent Activation; Adenylate Adrenergic, Analysis; Animals; Biological; C, Calcium Calcium-Binding Chains; Channels, Chemical; Cholera Cyclase, Cyclic Dose-Response Drug; Enzyme Factors Humans; Isoproterenol, Kinase Kinases, Kinetics; L-Type, Markov Models, Myocardium, Phosphorylation; Protein Proteins, Receptors, Relationship, Signal Systems Theoretical; Time Toxin, Transduction; beta, cytology/metabolism; metabolism; pharmacology; %N 48 %P 47997--48003 %R 10.1074/jbc.M308362200 %T Modeling beta-adrenergic control of cardiac myocyte contractility in silico. %U http://dx.doi.org/10.1074/jbc.M308362200 %V 278 %X 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.

@article{Sauc_2003_47997, 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.}, added-at = {2009-06-03T11:20:58.000+0200}, author = {Saucerman, Jeffrey J and Brunton, Laurence L and Michailova, Anushka P and McCulloch, Andrew D}, biburl = {https://www.bibsonomy.org/bibtex/219785e84daed651ce5fd4aa37249c6ce/hake}, description = {The whole bibliography file I use.}, doi = {10.1074/jbc.M308362200}, file = {Sauc_2003_47997.pdf:Sauc_2003_47997.pdf:PDF}, institution = {U CA San Diego, La Jolla}, interhash = {172a1b2a025b89ab878d2744c9a30cfb}, intrahash = {19785e84daed651ce5fd4aa37249c6ce}, journal = {J Biol Chem}, keywords = {AMP, AMP-Dependent Activation; Adenylate Adrenergic, Analysis; Animals; Biological; C, Calcium Calcium-Binding Chains; Channels, Chemical; Cholera Cyclase, Cyclic Dose-Response Drug; Enzyme Factors Humans; Isoproterenol, Kinase Kinases, Kinetics; L-Type, Markov Models, Myocardium, Phosphorylation; Protein Proteins, Receptors, Relationship, Signal Systems Theoretical; Time Toxin, Transduction; beta, cytology/metabolism; metabolism; pharmacology;}, month = Nov, number = 48, pages = {47997--48003}, pdf = {Sauc_2003_47997.pdf}, pii = {M308362200}, pmid = {12972422}, timestamp = {2009-06-03T11:21:28.000+0200}, title = {Modeling beta-adrenergic control of cardiac myocyte contractility in silico.}, url = {http://dx.doi.org/10.1074/jbc.M308362200}, volume = 278, year = 2003 }