Protein phosphatase 2A-negative regulation of the protective signaling pathway of Ca2+/CaM-dependent ERK activation in cerebral ischemia
| Autor: | Li-xin Li, Yun-jiao Chen, Jie Zhao, Xiao Han, HuiWen Wu, He-ping Tian, Jun Guo |
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| Rok vydání: | 2008 |
| Předmět: |
MAPK/ERK pathway
Male medicine.medical_specialty MAP Kinase Signaling System Phosphatase Down-Regulation Biology CREB Ceramides Brain Ischemia Dephosphorylation Rats Sprague-Dawley Cellular and Molecular Neuroscience chemistry.chemical_compound Internal medicine medicine Animals Protein Phosphatase 2 Enzyme Inhibitors Extracellular Signal-Regulated MAP Kinases Kinase Protein phosphatase 2 Okadaic acid Cell biology Rats Enzyme Activation Endocrinology chemistry Calcium-Calmodulin-Dependent Protein Kinases biology.protein Signal transduction Signal Transduction |
| Zdroj: | Journal of neuroscience research. 86(12) |
| ISSN: | 1097-4547 |
| Popis: | Extracellular-signal-regulated kinase (ERK) undergoes rapid inactivation following the intense activation evoked by cerebral ischemia and reperfusion. However, the precise mechanism of this inactivation has not been elucidated. To investigate how phosphatases regulate the ERK cascade following ischemia, the PP2A inhibitors cantharidin and okadaic acid were administrated to the CA1 subregion of the rat hippocampus. The resulting sustained ERK activity implies that PP2A is a major phosphatase contributing to the rapid inactivation, but not activation, of ERK following cerebral ischemia. The increase in PP2A activity induced by ceramide has a weak effect on the activation of Raf via dephosphorylation of Ser259 in response to ischemia. In contrast, ketamine (Keta) and cyclosporine A (CsA), two chemicals that block calcium signal in ischemia, decrease ERK activity by blocking Raf dephosphorylation of Ser259. We also observed that activation of an upstream protein, Ras-GRF, leads to calcium/calmodulin-dependent activation of the ERK signaling cascade in response to ischemic stimuli. In addition, the activity of cyclic AMP response element-binding protein (CREB) and estrogen receptor α (ERα), target proteins of ERK and protective elements against ischemic lesion, parallels the activity of ERK. These data indicate that PP2A plays a significant role in blocking the protective effect induced by the ERK kinase pathway and that fast inactivation of ERK is the result of cross talk between calcium/calmodulin-dependent, positively regulated signal cascades and a ceramide-dependent negative signaling pathway. © 2008 Wiley-Liss, Inc. |
| Databáze: | OpenAIRE |
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