A dual receptor crosstalk model of G-protein-coupled signal transduction

• Published in: PLoS computational biology Vol. 4; no. 9; p. e1000185
• Main Authors: Flaherty, Patrick, Radhakrishnan, Mala L, Dinh, Tuan, Rebres, Robert A, Roach, Tamara I, Jordan, Michael I, Arkin, Adam P
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 01.09.2008; Public Library of Science (PLoS)
• Subjects: Animals; BASIC BIOLOGICAL SCIENCES; Biochemistry & Molecular Biology; Biophysics/Cell Signaling and Trafficking Structures; Biophysics/Theory and Simulation; Calcium channels; Calcium Signaling; Cell Biology/Cell Signaling; Cell Line; Cell receptors; Cellular signal transduction; Complement C5a - metabolism; Computational Biology; Computational Biology/Systems Biology; Feedback, Physiological; Gene expression; Genetic aspects; GTP-Binding Protein alpha Subunits, Gi-Go - antagonists & inhibitors; GTP-Binding Protein alpha Subunits, Gi-Go - genetics; GTP-Binding Protein alpha Subunits, Gi-Go - metabolism; GTP-Binding Protein alpha Subunits, Gq-G11 - antagonists & inhibitors; GTP-Binding Protein alpha Subunits, Gq-G11 - genetics; GTP-Binding Protein alpha Subunits, Gq-G11 - metabolism; Kinases; Ligands; Macrophages - metabolism; Mathematical & Computational Biology; MATHEMATICS AND COMPUTING; Mathematics/Statistics; Mice; Models, Biological; Physiological aspects; Proteins; Receptor Cross-Talk - physiology; Receptors, G-Protein-Coupled - antagonists & inhibitors; Receptors, G-Protein-Coupled - genetics; Receptors, G-Protein-Coupled - metabolism; RNA Interference; Signal processing; Signal transduction; Signal Transduction - physiology; Uridine Diphosphate - metabolism; United States; Cell Line; Receptor Cross-Talk; Signal Transduction; Computational Biology; Receptors, G-Protein-Coupled; Macrophages; Complement C5a; Feedback, Physiological; Animals; RNA Interference; Models, Biological; GTP-Binding Protein alpha Subunits, Gq-G11; Uridine Diphosphate; GTP-Binding Protein alpha Subunits, Gi-Go; Ligands; Mice; Calcium Signaling
• ISSN: 1553-7358; 1553-734X; 1553-7358
• DOI: 10.1371/journal.pcbi.1000185

Macrophage cells that are stimulated by two different ligands that bind to G-protein-coupled receptors (GPCRs) usually respond as if the stimulus effects are additive, but for a minority of ligand combinations the response is synergistic. The G-protein-coupled receptor system integrates signaling cues from the environment to actuate cell morphology, gene expression, ion homeostasis, and other physiological states. We analyze the effects of the two signaling molecules complement factors 5a (C5a) and uridine diphosphate (UDP) on the intracellular second messenger calcium to elucidate the principles that govern the processing of multiple signals by GPCRs. We have developed a formal hypothesis, in the form of a kinetic model, for the mechanism of action of this GPCR signal transduction system using data obtained from RAW264.7 macrophage cells. Bayesian statistical methods are employed to represent uncertainty in both data and model parameters and formally tie the model to experimental data. When the model is also used as a tool in the design of experiments, it predicts a synergistic region in the calcium peak height dose response that results when cells are simultaneously stimulated by C5a and UDP. An analysis of the model reveals a potential mechanism for crosstalk between the Galphai-coupled C5a receptor and the Galphaq-coupled UDP receptor signaling systems that results in synergistic calcium release.