Modeling cardiac β-adrenergic signaling with normalized-Hill differential equations: comparison with a biochemical model
Tóm tắt
New approaches are needed for large-scale predictive modeling of cellular signaling networks. While mass action and enzyme kinetic approaches require extensive biochemical data, current logic-based approaches are used primarily for qualitative predictions and have lacked direct quantitative comparison with biochemical models. We developed a logic-based differential equation modeling approach for cell signaling networks based on normalized Hill activation/inhibition functions controlled by logical AND and OR operators to characterize signaling crosstalk. Using this approach, we modeled the cardiac β1-adrenergic signaling network, including 36 reactions and 25 species. Direct comparison of this model to an extensively characterized and validated biochemical model of the same network revealed that the new model gave reasonably accurate predictions of key network properties, even with default parameters. Normalized Hill functions improved quantitative predictions of global functional relationships compared with prior logic-based approaches. Comprehensive sensitivity analysis revealed the significant role of PKA negative feedback on upstream signaling and the importance of phosphodiesterases as key negative regulators of the network. The model was then extended to incorporate recently identified protein interaction data involving integrin-mediated mechanotransduction. The normalized-Hill differential equation modeling approach allows quantitative prediction of network functional relationships and dynamics, even in systems with limited biochemical data.
Tài liệu tham khảo
Kiuchi K, Sato N, Shannon RP, Vatner DE, Morgan K, Vatner SF: Depressed beta-adrenergic receptor- and endothelium-mediated vasodilation in conscious dogs with heart failure. Circ Res. 1993, 73 (6): 1013-1023.
Brodde OE: Beta-adrenoceptors in cardiac disease. Pharmacol Ther. 1993, 60 (3): 405-430. 10.1016/0163-7258(93)90030-H
Bristow MR, Ginsburg R, Minobe W, Cubicciotti RS, Sageman WS, Lurie K, Billingham ME, Harrison DC, Stinson EB: Decreased catecholamine sensitivity and beta-adrenergic-receptor density in failing human hearts. N Engl J Med. 1982, 307 (4): 205-211. 10.1056/NEJM198207223070401
Brodde OE, Michel MC: Adrenergic and muscarinic receptors in the human heart. Pharmacol Rev. 1999, 51 (4): 651-690.
Engelhardt S, Bohm M, Erdmann E, Lohse MJ: Analysis of beta-adrenergic receptor mRNA levels in human ventricular biopsy specimens by quantitative polymerase chain reactions: progressive reduction of beta 1-adrenergic receptor mRNA in heart failure. J Am Coll Cardiol. 1996, 27 (1): 146-154. 10.1016/0735-1097(95)00425-4
Saucerman JJ, Brunton LL, Michailova AP, McCulloch AD: Modeling beta-adrenergic control of cardiac myocyte contractility in silico. J Biol Chem. 2003, 278 (48): 47997-48003. 10.1074/jbc.M308362200
Saucerman JJ, Healy SN, Belik ME, Puglisi JL, McCulloch AD: Proarrhythmic consequences of a KCNQ1 AKAP-binding domain mutation: computational models of whole cells and heterogeneous tissue. Circ Res. 2004, 95 (12): 1216-1224. 10.1161/01.RES.0000150055.06226.4e
Saucerman JJ, McCulloch AD: Cardiac beta-adrenergic signaling: from subcellular microdomains to heart failure. Ann N Y Acad Sci. 2006, 1080: 348-361. 10.1196/annals.1380.026
Albert I, Thakar J, Li S, Zhang R, Albert R: Boolean network simulations for life scientists. Source Code Biol Med. 2008, 3: 16- 10.1186/1751-0473-3-16
Aldridge BB, Saez-Rodriguez J, Muhlich JL, Sorger PK, Lauffenburger DA: Fuzzy logic analysis of kinase pathway crosstalk in TNF/EGF/insulin-induced signaling. PLoS Comput Biol. 2009, 5 (4): e1000340- 10.1371/journal.pcbi.1000340
Papin JA, Price ND, Palsson BO: Extreme pathway lengths and reaction participation in genome-scale metabolic networks. Genome Res. 2002, 12 (12): 1889-1900. 10.1101/gr.327702
Klamt S, Stelling J: Two approaches for metabolic pathway analysis?. Trends Biotechnol. 2003, 21 (2): 64-69. 10.1016/S0167-7799(02)00034-3
Klemm K, Bornholdt S: Stable and unstable attractors in Boolean networks. Phys Rev E Stat Nonlin Soft Matter Phys. 2005, 72 (5 Pt 2): 055101-
Ruths D, Muller M, Tseng JT, Nakhleh L, Ram PT: The signaling petri net-based simulator: a non-parametric strategy for characterizing the dynamics of cell-specific signaling networks. PLoS Comput Biol. 2008, 4 (2): e1000005- 10.1371/journal.pcbi.1000005
Chaves M, Sontag ED, Albert R: Methods of robustness analysis for Boolean models of gene control networks. Syst Biol (Stevenage). 2006, 153 (4): 154-167.
Morris MK, Saez-Rodriguez J, Sorger PK, Lauffenburger DA: Logic-based models for the analysis of cell signaling networks. Biochemistry. 2010, 49 (15): 3216-3224. 10.1021/bi902202q
Glass L, Kauffman SA: The logical analysis of continuous, non-linear biochemical control networks. J Theor Biol. 1973, 39 (1): 103-129. 10.1016/0022-5193(73)90208-7
Wittmann DM, Krumsiek J, Saez-Rodriguez J, Lauffenburger DA, Klamt S, Theis FJ: Transforming Boolean models to continuous models: methodology and application to T-cell receptor signaling. BMC Syst Biol. 2009, 3 (1): 98- 10.1186/1752-0509-3-98
Saucerman JJ, Zhang J, Martin JC, Peng LX, Stenbit AE, Tsien RY, McCulloch AD: Systems analysis of PKA-mediated phosphorylation gradients in live cardiac myocytes. Proc Natl Acad Sci USA. 2006, 103 (34): 12923-12928. 10.1073/pnas.0600137103
Bers DM: Cardiac excitation-contraction coupling. Nature. 2002, 415 (6868): 198-205. 10.1038/415198a
Vila Petroff MG, Egan JM, Wang X, Sollott SJ: Glucagon-like peptide-1 increases cAMP but fails to augment contraction in adult rat cardiac myocytes. Circ Res. 2001, 89 (5): 445-452. 10.1161/hh1701.095716
Hausdorff WP, Caron MG, Lefkowitz RJ: Turning off the signal: desensitization of beta-adrenergic receptor function. FASEB J. 1990, 4 (11): 2881-2889.
Hagemann D, Kuschel M, Kuramochi T, Zhu W, Cheng H, Xiao RP: Frequency-encoding Thr17 phospholamban phosphorylation is independent of Ser16 phosphorylation in cardiac myocytes. J Biol Chem. 2000, 275 (29): 22532-22536. 10.1074/jbc.C000253200
Laflamme MA, Becker PL: Do beta 2-adrenergic receptors modulate Ca2+ in adult rat ventricular myocytes?. Am J Physiol. 1998, 274 (4 Pt 2): H1308-1314.
Yakoby N, Lembong J, Schupbach T, Shvartsman SY: Drosophila eggshell is patterned by sequential action of feedforward and feedback loops. Development. 2008, 135 (2): 343-351. 10.1242/dev.008920
Xin W, Tran TM, Richter W, Clark RB, Rich TC: Roles of GRK and PDE4 activities in the regulation of beta2 adrenergic signaling. J Gen Physiol. 2008, 131 (4): 349-364. 10.1085/jgp.200709881
Violin JD, DiPilato LM, Yildirim N, Elston TC, Zhang J, Lefkowitz RJ: beta2-adrenergic receptor signaling and desensitization elucidated by quantitative modeling of real time cAMP dynamics. J Biol Chem. 2008, 283 (5): 2949-2961. 10.1074/jbc.M707009200
Rapacciuolo A, Suvarna S, Barki-Harrington L, Luttrell LM, Cong M, Lefkowitz RJ, Rockman HA: Protein kinase A and G protein-coupled receptor kinase phosphorylation mediates beta-1 adrenergic receptor endocytosis through different pathways. J Biol Chem. 2003, 278 (37): 35403-35411. 10.1074/jbc.M305675200
Packer M: Effect of phosphodiesterase inhibitors on survival of patients with chronic congestive heart failure. Am J Cardiol. 1989, 63 (2): 41A-45A. 10.1016/0002-9149(89)90392-5
Endoh M, Hori M: Acute heart failure: inotropic agents and their clinical uses. Expert Opin Pharmacother. 2006, 7 (16): 2179-2202. 10.1517/14656566.7.16.2179
Packer M, Carver JR, Rodeheffer RJ, Ivanhoe RJ, DiBianco R, Zeldis SM, Hendrix GH, Bommer WJ, Elkayam U, Kukin ML, et al.: Effect of oral milrinone on mortality in severe chronic heart failure. The PROMISE Study Research Group. N Engl J Med. 1991, 325 (21): 1468-1475. 10.1056/NEJM199111213252103
Jones SL: Protein kinase A regulates beta2 integrin avidity in neutrophils. J Leukoc Biol. 2002, 71 (6): 1042-1048.
Alenghat FJ, Tytell JD, Thodeti CK, Derrien A, Ingber DE: Mechanical control of cAMP signaling through integrins is mediated by the heterotrimeric Galphas protein. J Cell Biochem. 2009, 106 (4): 529-538. 10.1002/jcb.22001
Todaka K, Ogino K, Gu A, Burkhoff D: Effect of ventricular stretch on contractile strength, calcium transient, and cAMP in intact canine hearts. Am J Physiol. 1998, 274 (3 Pt 2): H990-1000.
Carr AN, Schmidt AG, Suzuki Y, del Monte F, Sato Y, Lanner C, Breeden K, Jing SL, Allen PB, Greengard P, et al.: Type 1 phosphatase, a negative regulator of cardiac function. Mol Cell Biol. 2002, 22 (12): 4124-4135. 10.1128/MCB.22.12.4124-4135.2002
Van Tassell BW, Radwanski P, Movsesian M, Munger MA: Combination therapy with beta-adrenergic receptor antagonists and phosphodiesterase inhibitors for chronic heart failure. Pharmacotherapy. 2008, 28 (12): 1523-1530. 10.1592/phco.28.12.1523
Pal R, Datta A, Bittner ML, Dougherty ER: Intervention in context-sensitive probabilistic Boolean networks. Bioinformatics. 2005, 21 (7): 1211-1218. 10.1093/bioinformatics/bti131
Pomerance A, Ott E, Girvan M, Losert W: The effect of network topology on the stability of discrete state models of genetic control. Proc Natl Acad Sci USA. 2009, 106 (20): 8209-8214. 10.1073/pnas.0900142106
Albert R, Wang RS: Discrete dynamic modeling of cellular signaling networks. Methods in enzymology. 2009, 467: 281-306. full_text
Saroff HA, Yap WT: The action of hemoglobin. Cooperative effects in tetrameric proteins. Biopolymers. 1972, 11 (5): 957-971. 10.1002/bip.1972.360110504
Rosenfeld N, Young JW, Alon U, Swain PS, Elowitz MB: Accurate prediction of gene feedback circuit behavior from component properties. Mol Syst Biol. 2007, 3: 143- 10.1038/msb4100185
Aldridge BB, Burke JM, Lauffenburger DA, Sorger PK: Physicochemical modelling of cell signalling pathways. Nat Cell Biol. 2006, 8 (11): 1195-1203. 10.1038/ncb1497
Malmstrom J, Beck M, Schmidt A, Lange V, Deutsch EW, Aebersold R: Proteome-wide cellular protein concentrations of the human pathogen Leptospira interrogans. Nature. 2009, 460 (7256): 762-765. 10.1038/nature08184
Higham CF: Bifurcation analysis informs Bayesian inference in the Hes1 feedback loop. BMC Syst Biol. 2009, 3: 12- 10.1186/1752-0509-3-12
Bandara S, Schloder JP, Eils R, Bock HG, Meyer T: Optimal experimental design for parameter estimation of a cell signaling model. PLoS Comput Biol. 2009, 5 (11): e1000558- 10.1371/journal.pcbi.1000558
Bassingthwaighte J, Hunter P, Noble D: The Cardiac Physiome: perspectives for the future. Exp Physiol. 2009, 94 (5): 597-605. 10.1113/expphysiol.2008.044099