title: Modulation of the cAMP response by Gαi and Gβγ: a computational study of G protein signaling in immune cells.
abstract: Cyclic AMP is important for the resolution of inflammation, as it promotes anti-inflammatory signaling in several immune cell lines. In this paper, we present an immune cell specific model of the cAMP signaling cascade, paying close attention to the specific isoforms of adenylyl cyclase (AC) and phosphodiesterase that control cAMP production and degradation, respectively, in these cells. The model describes the role that G protein subunits, including Gαs, Gαi, and Gβγ, have in regulating cAMP production. Previously, Gαi activation has been shown to increase the level of cAMP in certain immune cell types. This increase in cAMP is thought to be mediated by βγ subunits which are released upon Gα activation and can directly stimulate specific isoforms of AC. We conduct numerical experiments in order to explore the mechanisms through which Gαi activation can increase cAMP production. An important conclusion of our analysis is that the relative abundance of different G protein subunits is an essential determinant of the cAMP profile in immune cells. In particular, our model predicts that limited availability of βγ subunits may both (i) enable immune cells to link inflammatory Gαi signaling to anti-inflammatory cAMP production thereby creating a balanced immune response to stimulation with low concentrations of PGE2, and (ii) prohibit robust anti-inflammatory cAMP signaling in response to stimulation with high concentrations of PGE2.
authors.affiliation: Department of Mathematics, Middle Tennessee State University, Murfreesboro, TN , 37132, USA, rachel.leander@mtsu.edu.
authors.forename: R
authors.initials: R
authors.lastname: Leander
authors.forename: A
authors.initials: A
authors.lastname: Friedman
mesh_terms: D000262:Adenylyl Cyclases / Q000276:immunology*; D002460:Cell Line; D003198:Computer Simulation; D000242:Cyclic AMP / Q000276:immunology*; D044385:GTP-Binding Protein alpha Subunits / Q000276:immunology; D044387:GTP-Binding Protein beta Subunits / Q000276:immunology; D044388:GTP-Binding Protein gamma Subunits / Q000276:immunology; D007700:Kinetics; D018448:Models, Immunological; D044087:Receptor, Anaphylatoxin C5a / Q000276:immunology; D058307:Receptors, Prostaglandin E, EP2 Subtype / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology*
chemical_list: C488033:C5AR1 protein, human; D044385:GTP-Binding Protein alpha Subunits; D044387:GTP-Binding Protein beta Subunits; D044388:GTP-Binding Protein gamma Subunits; D044087:Receptor, Anaphylatoxin C5a; D058307:Receptors, Prostaglandin E, EP2 Subtype; D000242:Cyclic AMP; D000262:Adenylyl Cyclases