title: Growth factor pre-treatment differentially regulates phosphoinositide turnover downstream of lysophospholipid receptor and metabotropic glutamate receptors in cultured rat cerebrocortical astrocytes.
abstract: Reactive gliosis is an aspect of neural plasticity and growth factor (GF) stimulation of astrocytes in vitro is widely regarded as a model system to study astrocyte plasticity. Astrocytes express receptors for several ligands including lysophosphatidic acid (LPA) and sphingosine-1-phosphate (S1P), agonists for the G-protein-coupled lysophospholipid receptors (lpRs). Activation of lpRs by LPA or S1P leads to multiple pharmacological effects including the influx of calcium, phosphoinositide (PI) hydrolysis, phosphorylation of extracellular receptor regulated kinase (ERK), release of arachidonic acid, and induces mitogenesis. Treatment of astrocytes in vitro with a growth factor cocktail (containing epidermal growth factor [EGF], basic fibroblast growth factor [bFGF] and insulin) led to a marked attenuation of lpR-induced PI hydrolysis. In contrast, under identical conditions, GF treatment led to marked potentiation of PI hydrolysis downstream of activation of another abundantly expressed G-protein coupled receptor, mGluR5. Quantitative gene expression analysis of GF-treated or control astrocytes by TaqMan RT-PCR indicated that GF treatment did not change gene expression of lpa1 and s1p1, but increased gene expression of s1p5 which is expressed at very low levels in basal conditions. These results suggest that GF differentially affected PLC activation downstream of mGluR5 versus lpR activation and that the changes in mRNA levels of lpRs do not account for marked attenuation of agonist-induced phosphoinositide turnover.
authors.affiliation: Merck Research Laboratories-San Diego, 3535 General Atomics Court, Bldg 1, San Diego, CA 92121, USA. trao@kalypsys.com
authors.forename: Tadimeti S
authors.initials: TS
authors.lastname: Rao
authors.forename: Karen D
authors.initials: KD
authors.lastname: Lariosa-Willingham
authors.forename: Fen-Fen
authors.initials: FF
authors.lastname: Lin
authors.forename: Naichen
authors.initials: N
authors.lastname: Yu
authors.forename: Chui-Se
authors.initials: CS
authors.lastname: Tham
authors.forename: Jerold
authors.initials: J
authors.lastname: Chun
authors.forename: Michael
authors.initials: M
authors.lastname: Webb
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000187:drug effects* / Q000378:metabolism*; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000187:drug effects* / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004815:Epidermal Growth Factor / Q000494:pharmacology; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology; D006133:Growth Substances / Q000494:pharmacology*; D006706:Homeostasis / Q000187:drug effects / Q000502:physiology; D007295:Inositol Phosphates / Q000378:metabolism; D007328:Insulin / Q000494:pharmacology; D010716:Phosphatidylinositols / Q000378:metabolism*; D010766:Phosphorylation; D051381:Rats; D017207:Rats, Sprague-Dawley; D064529:Receptor, Metabotropic Glutamate 5; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D049312:Receptors, Lysophospholipid; D018094:Receptors, Metabotropic Glutamate / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
chemical_list: C578937:Grm5 protein, rat; D006133:Growth Substances; D007295:Inositol Phosphates; D007328:Insulin; D010716:Phosphatidylinositols; D064529:Receptor, Metabotropic Glutamate 5; D043562:Receptors, G-Protein-Coupled; D049312:Receptors, Lysophospholipid; D018094:Receptors, Metabotropic Glutamate; D016222:Fibroblast Growth Factor 2; D004815:Epidermal Growth Factor