%0 Journal Article %1 Gree_2004_16 %A Greenstein, Joseph L %A Tanskanen, Antti J %A Winslow, Raimond L %D 2004 %J Ann. N. Y. Acad. Sci. %K AMP-Dependent Acid Action Adaptor Adrenergic, Algorithms, Amino Animals, Biological, Biophysics, Calcium Calcium, Cardiac, Cardiovascular, Cell Cells, Chains, Channel Channel, Channels, Comparative Complexes, Computer Conduction Contraction, Cyclic Dependent Dogs, Electrophysiology, Expression Extramural, Factors, Gating, Gene Gov't, Guinea Heart Humans, Interaction Ion Ions, Isoproterenol, Kinase, Kinases, L-Type, Long Mapping, Markov Membrane Membrane, Models, Multiprotein Muscle Myocardial Myocardium, Myocytes, N.I.H., Neurons, Non-U.S. P.H.S., Phosphatase, Phosphoprotein Phosphorylation, Pigs, Post-Translational, Potassium Potentials, Processes, Processing, Profiling, Protein Proteins, Proteome, Proteomics, QT Receptor Receptors, Regulation, Relationship, Release Research Ryanodine Ryanodine, Signal Signaling, Simulation, Stochastic Structure-Activity Study, Substitution, Support, Syndrome, System, Time Transducing, Transduction, U.S. Ventricles, Voltage-Gated, beta, {C}a$^{2+}$-Calmodulin %P 16--27 %R 10.1196/annals.1302.002 %T Modeling the actions of beta-adrenergic signaling on excitation--contraction coupling processes. %U http://dx.doi.org/10.1196/annals.1302.002 %V 1015 %X Activation of the beta-adrenergic (beta-AR) signaling pathway enhances cardiac function through protein kinase A (PKA)-mediated phosphorylation of target proteins involved in the process of excitation-contraction (EC) coupling. Experimental studies of the effects of beta-AR stimulation on EC coupling have yielded complex results, including increased, decreased, or unchanged EC coupling gain. In this study, we extend a previously developed model of the canine ventricular myocyte describing local control of sarcoplasmic reticulum (SR) calcium (Ca$^2+$) release to include the effects of beta-AR stimulation. Incorporation of phosphorylation-dependent effects on model membrane currents and Ca$^2+$-cycling proteins yields changes of action potential (AP) and Ca$^2+$ transients in agreement with those measured experimentally in response to the nonspecific beta-AR agonist isoproterenol (ISO). The model reproduces experimentally observed alterations in EC coupling gain in response to beta-AR agonists and predicts the specific roles of L-type Ca$^2+$ channel (LCC) and SR Ca$^2+$ release channel phosphorylation in altering the amplitude and shape of the EC coupling gain function. The model also indicates that factors that promote mode 2 gating of LCCs, such as beta-AR stimulation or activation of the Ca$^2+$/calmodulin-dependent protein kinase II (CaMKII), may increase the probability of occurrence of early after-depolarizations (EADs), due to the random, long-duration opening of LCC gating in mode 2.

@article{Gree_2004_16, abstract = {Activation of the beta-adrenergic (beta-AR) signaling pathway enhances cardiac function through protein kinase A ({PKA})-mediated phosphorylation of target proteins involved in the process of excitation-contraction (EC) coupling. Experimental studies of the effects of beta-AR stimulation on EC coupling have yielded complex results, including increased, decreased, or unchanged EC coupling gain. In this study, we extend a previously developed model of the canine ventricular myocyte describing local control of sarcoplasmic reticulum (SR) calcium ({C}a$^{2+}$) release to include the effects of beta-AR stimulation. Incorporation of phosphorylation-dependent effects on model membrane currents and {C}a$^{2+}$-cycling proteins yields changes of action potential (AP) and {C}a$^{2+}$ transients in agreement with those measured experimentally in response to the nonspecific beta-AR agonist isoproterenol ({ISO}). The model reproduces experimentally observed alterations in EC coupling gain in response to beta-AR agonists and predicts the specific roles of L-type {C}a$^{2+}$ channel (LCC) and SR {C}a$^{2+}$ release channel phosphorylation in altering the amplitude and shape of the EC coupling gain function. The model also indicates that factors that promote mode 2 gating of LCCs, such as beta-AR stimulation or activation of the {C}a$^{2+}$/calmodulin-dependent protein kinase II (CaMKII), may increase the probability of occurrence of early after-depolarizations (EADs), due to the random, long-duration opening of LCC gating in mode 2.}, added-at = {2009-06-03T11:20:58.000+0200}, author = {Greenstein, Joseph L and Tanskanen, Antti J and Winslow, Raimond L}, biburl = {https://www.bibsonomy.org/bibtex/2f8defeee6f1da046413d9c8bf5e93af7/hake}, description = {The whole bibliography file I use.}, doi = {10.1196/annals.1302.002}, file = {Gree_2004_16.pdf:Gree_2004_16.pdf:PDF}, interhash = {966b0a0e528e2393c379de2803083982}, intrahash = {f8defeee6f1da046413d9c8bf5e93af7}, journal = {Ann. N. Y. Acad. Sci.}, keywords = {AMP-Dependent Acid Action Adaptor Adrenergic, Algorithms, Amino Animals, Biological, Biophysics, Calcium Calcium, Cardiac, Cardiovascular, Cell Cells, Chains, Channel Channel, Channels, Comparative Complexes, Computer Conduction Contraction, Cyclic Dependent Dogs, Electrophysiology, Expression Extramural, Factors, Gating, Gene Gov't, Guinea Heart Humans, Interaction Ion Ions, Isoproterenol, Kinase, Kinases, L-Type, Long Mapping, Markov Membrane Membrane, Models, Multiprotein Muscle Myocardial Myocardium, Myocytes, N.I.H., Neurons, Non-U.S. P.H.S., Phosphatase, Phosphoprotein Phosphorylation, Pigs, Post-Translational, Potassium Potentials, Processes, Processing, Profiling, Protein Proteins, Proteome, Proteomics, QT Receptor Receptors, Regulation, Relationship, Release Research Ryanodine Ryanodine, Signal Signaling, Simulation, Stochastic Structure-Activity Study, Substitution, Support, Syndrome, System, Time Transducing, Transduction, U.S. Ventricles, Voltage-Gated, beta, {C}a$^{2+}$-Calmodulin}, month = May, pages = {16--27}, pii = {1015/1/16}, pmid = {15201146}, timestamp = {2009-06-03T11:21:13.000+0200}, title = {Modeling the actions of beta-adrenergic signaling on excitation--contraction coupling processes.}, url = {http://dx.doi.org/10.1196/annals.1302.002}, volume = 1015, year = 2004 }