title: Cell shape and negative links in regulatory motifs together control spatial information flow in signaling networks.
abstract: The role of cell size and shape in controlling local intracellular signaling reactions, and how this spatial information originates and is propagated, is not well understood. We have used partial differential equations to model the flow of spatial information from the beta-adrenergic receptor to MAPK1,2 through the cAMP/PKA/B-Raf/MAPK1,2 network in neurons using real geometries. The numerical simulations indicated that cell shape controls the dynamics of local biochemical activity of signal-modulated negative regulators, such as phosphodiesterases and protein phosphatases within regulatory loops to determine the size of microdomains of activated signaling components. The model prediction that negative regulators control the flow of spatial information to downstream components was verified experimentally in rat hippocampal slices. These results suggest a mechanism by which cellular geometry, the presence of regulatory loops with negative regulators, and key reaction rates all together control spatial information transfer and microdomain characteristics within cells.
authors.affiliation: Department of Pharmacology and Systems Therapeutics, Mount Sinai School of Medicine, One Gustave L. Levy Place, Box 1215, New York, NY 10029, USA.
authors.forename: Susana R
authors.initials: SR
authors.lastname: Neves
authors.forename: Panayiotis
authors.initials: P
authors.lastname: Tsokas
authors.forename: Anamika
authors.initials: A
authors.lastname: Sarkar
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Grace
authors.forename: Padmini
authors.initials: P
authors.lastname: Rangamani
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Taubenfeld
authors.forename: Cristina M
authors.initials: CM
authors.lastname: Alberini
authors.forename: James C
authors.initials: JC
authors.lastname: Schaff
authors.forename: Robert D
authors.initials: RD
authors.lastname: Blitzer
authors.forename: Ion I
authors.initials: II
authors.lastname: Moraru
authors.forename: Ravi
authors.initials: R
authors.lastname: Iyengar
mesh_terms: D000818:Animals; D001048:Aplysia; D048430:Cell Shape; D000242:Cyclic AMP / Q000378:metabolism; D025461:Feedback, Physiological; D005333:Fetus; D006624:Hippocampus / Q000166:cytology; D007545:Isoproterenol / Q000378:metabolism; D020935:MAP Kinase Signaling System; D053858:Metabolic Networks and Pathways; D008954:Models, Biological; D009474:Neurons / Q000166:cytology / Q000201:enzymology / Q000378:metabolism*; D051381:Rats; D018343:Receptors, Adrenergic, beta-2 / Q000378:metabolism
chemical_list: D018343:Receptors, Adrenergic, beta-2; D000242:Cyclic AMP; D007545:Isoproterenol