inositol-1-4-5-trisphosphate and Hypersensitivity

Phosphoinositide 3-kinases (PI3Ks) control cell growth, proliferation, cell survival, metabolic activity, vesicular trafficking, degranulation, and migration. Through these processes, PI3Ks modulate vital physiology. When over-activated in disease, PI3K promotes tumor growth, angiogenesis, metastasis or excessive immune cell activation in inflammation, allergy and autoimmunity. This chapter will introduce molecular activation and signaling of PI3Ks, and connections to target of rapamycin (TOR) and PI3K-related protein kinases (PIKKs). The focus will be on class I PI3Ks, and extend into current developments to exploit mechanistic knowledge for therapy.

Topics: Autoimmunity; Cell Transformation, Neoplastic; Diglycerides; Enzyme Inhibitors; Eukaryotic Cells; Gene Expression Regulation, Neoplastic; Humans; Hypersensitivity; Inositol 1,4,5-Trisphosphate; Isoenzymes; Neoplasms; Phosphatidylinositol 3-Kinases; Phosphatidylinositol 4,5-Diphosphate; Phosphoinositide-3 Kinase Inhibitors; Second Messenger Systems; TOR Serine-Threonine Kinases

Antigen/IgE-mediated mast cell activation via FcvarepsilonRI can be markedly enhanced by the activation of other receptors expressed on mast cells and these receptors may thus contribute to the allergic response in vivo. One such receptor family is the G protein-coupled receptors (GPCRs). Although the signaling cascade linking FcvarepsilonRI aggregation to mast cell activation has been extensively investigated, the mechanisms by which GPCRs amplify this response are relatively unknown. To investigate this, we utilized prostaglandin (PG)E2 based on initial studies demonstrating its greater ability to augment antigen-mediated degranulation in mouse mast cells than other GPCR agonists examined. This enhancement, and the ability of PGE2 to amplify antigen-induced calcium mobilization, was independent of phosphoinositide 3-kinase but was linked to a pertussis toxin-sensitive synergistic translocation to the membrane of phospholipase (PL)Cgamma and PLCbeta and to an enhancement of PLCgamma phosphorylation. This "trans-synergistic" activation of PLCbeta and gamma, in turn, enhanced production of inositol 1,4,5-trisphosphate, store-operated calcium entry, and activation of protein kinase C (PKC) (alpha and beta). These responses were critical for the promotion of degranulation. This is the first report of synergistic activation between PLCgamma and PLCbeta that permits reinforcement of signals for degranulation in mast cells.

Topics: Animals; Antigens; Calcium Signaling; Cell Degranulation; Cell Membrane; Cells, Cultured; Cytokines; Dinoprostone; Enzyme Activation; Hypersensitivity; Inositol 1,4,5-Trisphosphate; Macrophages; Mice; Mice, Inbred C57BL; Pertussis Toxin; Phosphatidylinositol 3-Kinases; Phospholipase C beta; Phospholipase C gamma; Phosphorylation; Protein Kinase C; Protein Kinase C beta; Protein Kinase C-alpha; Protein Transport; Receptor Aggregation; Receptor Cross-Talk; Receptors, IgE; Receptors, Prostaglandin E; Signal Transduction; Time Factors