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Down‐regulation of GRK2 after oxygen and glucose deprivation in rat hippocampal slices: role of the PI3‐kinase pathway
Author(s) -
Lombardi Maria Stella,
Vroon Anne,
Sodaar Peter,
Van Muiswinkel Freek L.,
Heijnen Cobi J.,
Kavelaars Annemieke
Publication year - 2007
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2007.04576.x
Subject(s) - beta adrenergic receptor kinase , g protein coupled receptor kinase , mg132 , kinase , microbiology and biotechnology , phosphorylation , biology , signal transduction , wortmannin , protein kinase a , chemistry , medicine , proteasome inhibitor , proteasome , g protein , phosphatidylinositol , g protein coupled receptor
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.