Cross-Talk among Intracellular Signaling Pathways Mediates the Diphenyl Ditelluride Actions on the Hippocampal Cytoskeleton of Young Rats

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• 作者：Luana Heimfarth ; Samanta Oliveira Loureiro ; Karina Pires Reis ; B谩rbara Ortiz de Lima ; Fernanda Zamboni ; Talita Gandolfi ; Rodrigo Narvaes ; Jo茫o Batista Teixeira da Rocha ; Regina Pessoa-Pureur
• 刊名：Chemical Research in Toxicology
• 出版年：2011
• 出版时间：October 17, 2011
• 年：2011
• 卷：24
• 期：10
• 页码：1754-1764
• 全文大小：1040K
• 年卷期：v.24,no.10(October 17, 2011)
• ISSN：1520-5010

文摘

In the present report, we showed that diphenyl ditelluride (PhTe)₂ induced in vitro hyperphosphorylation of glial fibrillary acidic protein (GFAP), vimentin and neurofilament (NF) subunits in hippocampus of 21 day-old rats. Hyperphosphorylation was dependent on L-voltage dependent Ca²⁺ channels (L-VDCC), N-methyl-d-aspartate (NMDA) and metabotropic glutamate receptors, as demonstrated by the specific inhibitors verapamil, DL-AP5 and MCPG, respectively. Also, dantrolene, a ryanodine channel blocker, EGTA and Bapta-AM, extra and intracellular Ca²⁺ chelators respectively, totally prevented this effect. Activation of metabotropic glutamate receptors by (PhTe)₂ upregulates phospholipase C (PLC), producing inositol 1, 4, 5-trisphosphate (IP₃) and diacylglycerol (DAG). Therefore, high Ca²⁺ levels and DAG directly activate Ca²⁺/calmodulin-dependent protein kinase (PKCaMII) and protein kinase C (PCK), resulting in the hyperphosphorylation of Ser-57 in the carboxyl-terminal tail domain of the low molecular weight NF subunit (NF-L). Also, the activation of Erk1/2, and p38MAPK resulted in hyperphosphorylation of KSP repeats of the medium molecular weight NF subunit (NF-M). It is noteworthy that PKCaMII and PKC inhibitors prevented (PhTe)₂-induced Erk1/2MAPK and p38MAPK activation as well as hyperphosphorylation of KSP repeats on NF-M, suggesting that PKCaMII and PKC could be upstream of this activation. Taken together, our results highlight the role of Ca²⁺ as a mediator of the (PhTe)₂-elicited signaling targeting specific phosphorylation sites on IF proteins of neural cells of rat hippocampus. Interestingly, this action shows a significant cross-talk among signaling pathways elicited by (PhTe)₂, connecting glutamate metabotropic cascade with activation of Ca²⁺ channels. The extensively phosphorylated amino- and carboxyl- terminal sites could explain, at least in part, the neural dysfunction associated with (PhTe)₂ exposure