PICK1-mediated GluR2 endocytosis contributes to cellular injury after neuronal trauma
| العنوان: | PICK1-mediated GluR2 endocytosis contributes to cellular injury after neuronal trauma |
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| المؤلفون: | Jinglu Ai, Andrew J. Baker, Eugene Park, Joshua D. Bell |
| المصدر: | Cell Death & Differentiation. 16:1665-1680 |
| بيانات النشر: | Springer Science and Business Media LLC, 2009. |
| سنة النشر: | 2009 |
| مصطلحات موضوعية: | Cell signaling, N-Methylaspartate, media_common.quotation_subject, Excitotoxicity, AMPA receptor, Biology, medicine.disease_cause, Tissue Culture Techniques, medicine, Animals, Receptors, AMPA, Rats, Wistar, Internalization, Molecular Biology, Cells, Cultured, media_common, Glutamate receptor, Nuclear Proteins, Cell Biology, Endocytosis, Rats, Cell biology, Cytoskeletal Proteins, Protein Transport, nervous system, Brain Injuries, Immunology, NMDA receptor, Carrier Proteins, Neuron death, PICK1, Protein Binding |
| الوصف: | Constitutive and activity-dependent regulation of the AMPA receptor GluR2 content is recognized as an important mediator of both neuronal plasticity and vulnerability to excitotoxic neuron death. In the latter case, inclusion of GluR2 protects against glutamate excitotoxicity in CNS disease by lowering receptor single-channel conductance and preventing deleterious calcium influx. We investigated the hypothesis that aberrations in GluR2 trafficking after in vitro and in vivo cerebral trauma contribute to excitotoxicity and associated calcium-dependent cell death processes. First, in an in vitro model of traumatic brain injury (TBI), we observed PICK1 and N-methyl-D-aspartic acid (NMDA) receptor-dependent phosphorylation and internalization of GluR2. The contributing cell signaling mechanisms involved enhanced binding between PKCalpha (the kinase that phosphorylates GluR2) and PICK1 (its PDZ-binding partner), and a novel protein interaction between PKCalpha and the NMDA receptor scaffolding protein PSD-95. Functionally, these phenomena enhanced single cell AMPAR mEPSCs and protracted calcium extrusion. In vivo TBI similarly promoted GluR2 phosphorylation and internalization, with enhanced expression of calcium-permeable AMPARs in the injured hippocampus. Peptide-mediated perturbation of the PKCalpha/PICK1 protein interaction after trauma preserved surface GluR2 expression, attenuated AMPAR-mediated toxicity, and occluded the sensitivity of neuronal physiology to calcium-permeable AMPAR antagonists. These findings suggest that experimental TBI promotes the expression of injurious GluR2-lacking AMPARs, thereby enhancing cellular vulnerability to secondary excitotoxicity. |
| تدمد: | 1476-5403 1350-9047 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::91eb140cdb3dad515785ba1d51f57960Test https://doi.org/10.1038/cdd.2009.106Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....91eb140cdb3dad515785ba1d51f57960 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 14765403 13509047 |
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