Down-regulation of GRK2 after oxygen and glucose deprivation in rat hippocampal slices: role of the PI3-kinase pathway
| Autor: | Maria Stella, Lombardi, Anne, Vroon, Peter, Sodaar, Freek L, van Muiswinkel, Cobi J, Heijnen, Annemieke, Kavelaars |
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| Rok vydání: | 2007 |
| Předmět: |
Proteasome Endopeptidase Complex
G-Protein-Coupled Receptor Kinase 2 Down-Regulation Hippocampus Rats Phosphatidylinositol 3-Kinases Glucose Organ Culture Techniques Animals Newborn beta-Adrenergic Receptor Kinases Hypoxia-Ischemia Brain Serine Animals RNA Messenger Enzyme Inhibitors Rats Wistar Extracellular Signal-Regulated MAP Kinases Proteasome Inhibitors Phosphoinositide-3 Kinase Inhibitors Signal Transduction |
| Zdroj: | Journal of neurochemistry. 102(3) |
| ISSN: | 0022-3042 |
| Popis: | G protein-coupled receptor kinase 2 (GRK2) modulates G protein-coupled receptor desensitization and signaling. We previously described down-regulation of GRK2 expression in vivo in rat neonatal brain following hypoxia-ischemia. In this study, we investigated the molecular mechanisms involved in GRK2 down-regulation, using organotypic cultures of neonatal rat hippocampal slices exposed to oxygen and glucose deprivation (OGD). We observed a 40% decrease in GRK2 expression 4 h post-OGD. No changes in GRK2 protein occurred after exposure of hippocampal slices to glucose deprivation only. No significant alterations in GRK2 mRNA expression were detected, suggesting a post-transcriptional effect of OGD on GRK2 expression. Blockade of the proteasome pathway by MG132 prevented OGD-induced decrease of GRK2. It has been shown that extracellular signal-regulated kinase-dependent phosphorylation of GRK2 at Ser670 triggers its turnover via the proteasome pathway. However, despite a significant increase of pSer670-GRK2 after OGD, inhibition of the extracellular signal-regulated kinase pathway by PD98059 did neither prevent the hypoxia-ischemia-induced increase in pSer670-GRK2 nor the down-regulation of GRK2 protein. Interestingly, inhibition of phosphoinositide-3-kinase with wortmannin inhibits both OGD-induced phosphorylation of GRK2 on Ser670 and the GRK2 decrease. In conclusion, OGD-induced phosphoinositide-3-kinase-dependent phosphorylation of GRK2 on Ser670 is a novel mechanism leading to down-regulation of GRK2 protein via a proteasome-dependent pathway. |
| Databáze: | OpenAIRE |
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