Premium
Stimulating ERK/PI3K/NFκB signaling pathways upon activation of mGluR2/3 restores OGD‐induced impairment in glutamate clearance in astrocytes
Author(s) -
Lin ChiaHo,
You JieRu,
Wei KaiChe,
Gean PoWu
Publication year - 2014
Publication title -
european journal of neuroscience
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.346
H-Index - 206
eISSN - 1460-9568
pISSN - 0953-816X
DOI - 10.1111/ejn.12383
Subject(s) - mapk/erk pathway , pyrrolidine dithiocarbamate , glutamate receptor , pi3k/akt/mtor pathway , signal transduction , ly294002 , astrocyte , metabotropic glutamate receptor , extracellular , microbiology and biotechnology , pharmacology , kinase , chemistry , metabotropic glutamate receptor 2 , nf κb , biology , receptor , biochemistry , endocrinology , central nervous system
We used the oxygen and glucose deprivation ( OGD ) method in cultured astrocytes as an in vitro ischemic model. We investigated whether activation of group‐II metabotropic glutamate receptors ( mG luR2/3) can reverse OGD ‐induced impairment in astrocytic glutamate/aspartate transporter ( GLAST ) expression and elucidated the signaling pathways involving the GLAST expression. Cultured astrocytes exposed to OGD for 6 h resulted in significant reductions in the GLAST expression and extracellular glutamate clearance. These reductions were effectively restored by mG luR2/3 activation with mG luR2/3 agonists, LY379268 or DCG ‐ IV , after the 6 h OGD insult. These mG luR2/3‐mediated restorative effects were inhibited by selective mG luR2/3 antagonists LY341459 or EGLU . The mG luR2/3 activation also induced activations of signaling pathways including extracellular signal‐regulated kinase ( ERK ), phosphatidylinositol 3‐kinase (PI3K) and nuclear transcription factor‐κB (NFκB). These activations were prevented by blocking mG luR2/3 with LY341459, an mG luR2/3 antagonist. Furthermore, blocking ERK , PI3K and NFκB signaling pathways with U0126, LY294002 and pyrrolidine dithiocarbamate, respectively, significantly inhibited the mG luR2/3‐mediated restorative effects. These results suggest that application of mG luR2/3 agonists after OGD insult can effectively reverse the OGD ‐reduced expression of GLAST proteins and restore clearance of extracellular glutamate by serially activating ERK/PI3K/NFκB signaling pathways in cultured astrocytes.