title: Cross-talk among intracellular signaling pathways mediates the diphenyl ditelluride actions on the hippocampal cytoskeleton of young rats.
abstract: 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 Ca(2+) 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 Ca(2+) chelators respectively, totally prevented this effect. Activation of metabotropic glutamate receptors by (PhTe)(2) upregulates phospholipase C (PLC), producing inositol 1, 4, 5-trisphosphate (IP(3)) and diacylglycerol (DAG). Therefore, high Ca(2+) levels and DAG directly activate Ca(2+)/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 Ca(2+) 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 Ca(2+) channels. The extensively phosphorylated amino- and carboxyl- terminal sites could explain, at least in part, the neural dysfunction associated with (PhTe)(2) exposure.
authors: Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde , Universidade Federal de Rio Grande do Sul, Porto Alegre, RS, Brazil.
authors: Luana
authors: L
authors: Heimfarth
authors: Samanta Oliveira
authors: SO
authors: Loureiro
authors: Karina Pires
authors: KP
authors: Reis
authors: Bárbara Ortiz
authors: BO
authors: de Lima
authors: Fernanda
authors: F
authors: Zamboni
authors: Talita
authors: T
authors: Gandolfi
authors: Rodrigo
authors: R
authors: Narvaes
authors: João Batista Teixeira
authors: JB
authors: da Rocha
authors: Regina
authors: R
authors: Pessoa-Pureur
mesh_terms: D000818:Animals; D001555:Benzene Derivatives / Q000633:toxicity*; D001596:Benzylamines / Q000494:pharmacology; D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism*; D020746:Calcium Channels, L-Type / Q000378:metabolism; D002540:Cerebral Cortex / Q000187:drug effects; D003599:Cytoskeleton / Q000187:drug effects / Q000378:metabolism; D004591:Electrophoresis, Polyacrylamide Gel; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism*; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism; D066298:In Vitro Techniques; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016900:Neurofilament Proteins / Q000378:metabolism*; D009942:Organometallic Compounds / Q000633:toxicity*; D010766:Phosphorylation / Q000187:drug effects; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D051381:Rats; D017208:Rats, Wistar; D019311:Staurosporine / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology; D014746:Vimentin / Q000378:metabolism*; D000096926:Benzenesulfonamides
chemical_list: D001555:Benzene Derivatives; D001596:Benzylamines; D002118:Calcium; D020746:Calcium Channels, L-Type; D005904:Glial Fibrillary Acidic Protein; D020928:Mitogen-Activated Protein Kinases; D016900:Neurofilament Proteins; D009942:Organometallic Compounds; D011493:Protein Kinase C; D019311:Staurosporine; D013449:Sulfonamides; D014746:Vimentin; C434247:diphenylditelluride; C072105:KN 93; D000096926:Benzenesulfonamides