A dual receptor crosstalk model of G-protein-coupled signal transduction.
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.
Flaherty
Patrick
P
Department of Electrical Engineering and Computer Sciences, University of California Berkeley, Berkeley, California, United States of America.
Radhakrishnan
Mala L
ML
Dinh
Tuan
T
Rebres
Robert A
RA
Roach
Tamara I
TI
Jordan
Michael I
MI
Arkin
Adam P
AP
D000818:Animals; D020013:Calcium Signaling; D002460:Cell Line; D015936:Complement C5a / Q000378:metabolism; D019295:Computational Biology; D025461:Feedback, Physiological; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D008024:Ligands; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D008954:Models, Biological; D034622:RNA Interference; D020239:Receptor Cross-Talk / Q000502:physiology*; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D014530:Uridine Diphosphate / Q000378:metabolism
D008024:Ligands; D043562:Receptors, G-Protein-Coupled; D014530:Uridine Diphosphate; D015936:Complement C5a; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; D043802:GTP-Binding Protein alpha Subunits, Gq-G11