Antagonism of group I metabotropic glutamate receptors and PLC attenuates increases in inositol trisphosphate and reduces reactive gliosis in strain-injured astrocytes
Abbreviated Journal Title
intracellular free calcium; GFAP; IP3; reactive astrocytes; TBI; TRAUMATIC BRAIN-INJURY; STRETCH-INDUCED INJURY; INTRACELLULAR FREE; CALCIUM; PROTEIN-KINASE-C; CELL-DEATH; INDUCED NEUROTOXICITY; CULTURED; ASTROCYTES; CORTICAL-NEURONS; UP-REGULATION; RAT; Critical Care Medicine; Clinical Neurology; Neurosciences
We have previously found that in vitro traumatic injury uncouples IP3-mediated intracellular free calcium ([Ca2+](i)) signaling in astrocytes (Rzigalinski et al., 1998; Floyd et al., 2001). Since Group I metabotropic glutamate receptors (mGluRs) are coupled to IP3-mediated Ca2+ signaling, we investigated their role in the in vitro strain injury of cultured astrocytes. Astrocytes grown on Silastic membranes were labeled with H-3-myo-inositol and strain (stretch)-injured. Cells injured in the presence of LiCl to prevent inositol phosphate metabolism were acid extracted and inositol phosphates (IPx) isolated using anion exchange columns. Reactive gliosis was assessed as increased glial fibrillary acidic protein immunoreactivity (GFAP-IR). Pre- but not post-injury administration of (RS)-1-aminoindan-15-decarboxylic acid (AIDA) or (S)-4-carboxy-3-hydroxyphenylglycine (S4CH3HPG), both group I mGluR antagonists, attenuated injury-induced increases in IPx. Injury increased GFAP-IR in astrocytes at 24 and 48 h post injury, which was reduced or blocked by AIDA or inhibition of phospholipase C (PLC) with U73122. These findings suggest that strain injury activates Group I mGluRs, causing aberrant IPx production and uncoupling of the PLC signaling pathway. Changes in this signaling pathway may be related to induction of reactive gliosis. Additionally, our results suggest a complex physical coupling between G protein receptor, PLC, and IP3 receptor, in support of the conformational coupling model.
Journal of Neurotrauma
"Antagonism of group I metabotropic glutamate receptors and PLC attenuates increases in inositol trisphosphate and reduces reactive gliosis in strain-injured astrocytes" (2004). Faculty Bibliography 2000s. 4350.