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Title: The phosphorylation status and cytoskeletal remodeling of striatal astrocytes treated with quinolinic acid
Authors: Pierozan, Paula
Ferreira, Fernanda
Lima, Barbara Ortiz de
Fernandes, Carolina Goncalves
Monteforte, Priscila Totarelli [UNIFESP]
Medaglia, Natalia de Castro [UNIFESP]
Bincoletto, Claudia [UNIFESP]
Smaili, Soraya Soubhi [UNIFESP]
Pessoa-Pureur, Regina
Univ Fed Rio Grande do Sul
Universidade Federal de São Paulo (UNIFESP)
Keywords: Quinolinic acid
Cytoskeleton remodelling
Astrocyte, cell signaling
GFAP phosphorylation
Issue Date: 1-Apr-2014
Publisher: Elsevier B.V.
Citation: Experimental Cell Research. San Diego: Elsevier Inc, v. 322, n. 2, p. 313-323, 2014.
Abstract: Quinolinic acid (QUIN) is a glutamate agonist which markedly enhances the vulnerability of neural cells to excitotoxicity. QUIN is produced from the amino acid tryptophan through the kynurenine pathway (KP). Dysregulation of this pathway is associated with neurodegenerative conditions. in this study we treated striatal astrocytes in culture with QUIN and assayed the endogenous phosphorylating system associated with glial fibrillary acidic protein (GFAP) and vimentin as well as cytoskeletal remodeling. After 24 h incubation with 100 mu M QUIN, cells were exposed to P-32-orthophosphate and/or protein kinase A (PKA), protein kinase dependent of Ca2+/calmodulin II (PKCaMII) or protein kinase C (PKC) inhibitors, H89 (20 mu M), KN93 (10 mu M) and staurosporin (10 nM), respectively. Results showed that hyperphosphorylation was abrogated by PKA and PKC inhibitors but not by the PKCaMII inhibitor. the specific antagonists to ionotropic NMDA and non-NMDA (50 mu M DL-AP5 and CNQX, respectively) glutamate receptors as well as to metabotropic glutamate receptor (mGLUR; 50 mu M MCPG), mGLUR1 (100 mu M MPEP) and mGLUR5 (10 mu M 4C3HPG) prevented the hyperphosphorylation provoked by QUIN. Also, intra and extracellular Ca2+ quelators (1 mM EGTA; 10 mu M BAPTA-AM, respectively) prevented QUIN-mediated effect, while Ca2+ influx through voltage-dependent Ca2+ channel type L (L-VDCC) (blocker: 10 mu M verapamil) is not implicated in this effect. Morphological analysis showed dramatically altered actin cytoskeleton with concomitant change of morphology to fusiform and/or flattened cells with retracted cytoplasm and disruption of the GFAP meshwork, supporting misregulation of actin cytoskeleton. Both hyperphosphorylation and cytoskeletal remodeling were reversed 24 h after QUIN removal. Astrocytes are highly plastic cells and the vulnerability of astrocyte cytoskeleton may have important implications for understanding the neurotoxicity of QUIN in neurodegenerative disorders. (C) 2014 Elsevier Inc. All rights reserved.
ISSN: 0014-4827
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