title: Proteomic and systems biology analysis of monocytes exposed to securinine, a GABA(A) receptor antagonist and immune adjuvant.
abstract: Securinine, a GABA(A) receptor antagonist, has been reported to enhance monocyte cell killing of Coxiella burnetii without obvious adverse effects in vivo. We employed multiplex 2D gel electrophoresis using Zdyes, a new generation of covalently linked fluorescent differential protein detection dyes to analyze changes in the monocyte proteome in response to Securinine. Securinine antagonism of GABA(A) receptors triggers the activation of p38. We used the differential protein expression results to guide a search of the literature and network analysis software to construct a systems biology model of the effect of Securinine on monocytes. The model suggests that various metabolic modulators (fatty acid binding protein 5, inosine 5'-monophosphate dehydrogenase, and thioredoxin) are at least partially reshaping the metabolic landscape within the monocytes. The actin bundling protein L-plastin, and the Ca(2+) binding protein S100A4 also appear to have important roles in the immune response stimulated by Securinine. Fatty acid binding protein 5 (FABP5) may be involved in effecting lipid raft composition, inflammation, and hormonal regulation of monocytes, and the model suggests that FABP5 may be a central regulator of metabolism in activated monocytes. The model also suggests that the heat shock proteins have a significant impact on the monocyte immune response. The model provides a framework to guide future investigations into the mechanisms of Securinine action and with elaboration may help guide development of new types of immune adjuvants.
authors.affiliation: Department of Chemistry and Biochemistry, Montana State University, Bozeman, Montana, United States of America. mshipman@chemistry.montana.edu
authors.forename: Matt
authors.initials: M
authors.lastname: Shipman
authors.forename: Kirk
authors.initials: K
authors.lastname: Lubick
authors.forename: David
authors.initials: D
authors.lastname: Fouchard
authors.forename: Rajani
authors.initials: R
authors.lastname: Guram
authors.forename: Paul
authors.initials: P
authors.lastname: Grieco
authors.forename: Mark
authors.initials: M
authors.lastname: Jutila
authors.forename: Edward A
authors.initials: EA
authors.lastname: Dratz
mesh_terms: D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D017951:Antigen Presentation / Q000276:immunology; D001381:Azepines / Q000494:pharmacology*; D019295:Computational Biology / Q000379:methods; D015180:Electrophoresis, Gel, Two-Dimensional; D058787:GABA-A Receptor Antagonists / Q000494:pharmacology*; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism; D006576:Heterocyclic Compounds, 4 or More Rings / Q000494:pharmacology; D006572:Heterocyclic Compounds, Bridged-Ring; D007783:Lactones / Q000494:pharmacology*; D053858:Metabolic Networks and Pathways; D008954:Models, Biological; D009000:Monocytes / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism*; D010880:Piperidines / Q000494:pharmacology*; D020543:Proteome; D040901:Proteomics; D011963:Receptors, GABA-A / Q000378:metabolism*; D015398:Signal Transduction; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D000276:Adjuvants, Immunologic; D001381:Azepines; D058787:GABA-A Receptor Antagonists; D018840:HSP70 Heat-Shock Proteins; D018841:HSP90 Heat-Shock Proteins; D006576:Heterocyclic Compounds, 4 or More Rings; D006572:Heterocyclic Compounds, Bridged-Ring; D007783:Lactones; D010880:Piperidines; D020543:Proteome; D011963:Receptors, GABA-A; D048051:p38 Mitogen-Activated Protein Kinases; C000785:securinine