title: Homocysteine activates calcium-mediated cell signaling mechanisms targeting the cytoskeleton in rat hippocampus.
abstract: Homocysteine is considered to be neurotoxic and a risk factor for neurodegenerative diseases. Despite the increasing evidences of excitotoxic mechanisms of homocysteine (Hcy), little is known about the action of Hcy on the cytoskeleton. In this context, the aim of the present work was to investigate the signaling pathways involved in the mechanism of action of Hcy on cytoskeletal phosphorylation in cerebral cortex and hippocampus of rats during development. Results showed that 100 microM Hcy increased the intermediate filament (IF) phosphorylation only in 17-day-old rat hippocampal slices without affecting the cerebral cortex from 9- to 29-day-old animals. Stimulation of (45)Ca(2+) uptake supported the involvement of NMDA receptors and voltage-dependent channels in extracellular Ca(2+) flux, as well as Ca(2+) release from intracellular stores through inositol-3-phosphate and ryanodine receptors. Moreover, the mechanisms underlying the Hcy effect on hippocampus cytoskeleton involved the participation of phospholipase C, protein kinase C, mitogen-activated protein kinase, phosphoinositol-3 kinase and calcium/calmodulin-dependent protein kinase II. The Hcy-induced IF hyperphosphorylation was also related to G(i) protein and inhibition of cAMP levels. These findings demonstrate that Hcy at a concentration described to induce neurotoxicity activates the IF-associated phosphorylating system during development in hippocampal slices of rats through different cell signaling mechanisms. These results probably suggest that hippocampal rather than cortical cytoskeleton is susceptible to neurotoxical concentrations of Hcy during development and this could be involved in the neural damage characteristic of mild homocystinuric patients.
authors.affiliation: Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande so Sul, Rua Ramiro Barcelos 2600, Porto Alegre, RS, Brazil.
authors.forename: Samanta Oliveira
authors.initials: SO
authors.lastname: Loureiro
authors.forename: Luana
authors.initials: L
authors.lastname: Heimfarth
authors.forename: Priscila de Lima
authors.initials: Pde L
authors.lastname: Pelaez
authors.forename: Camila Simioni
authors.initials: CS
authors.lastname: Vanzin
authors.forename: Lilian
authors.initials: L
authors.lastname: Viana
authors.forename: Angela T S
authors.initials: AT
authors.lastname: Wyse
authors.forename: Regina
authors.initials: R
authors.lastname: Pessoa-Pureur
mesh_terms: D000818:Animals; D001596:Benzylamines / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling / Q000187:drug effects; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism; D003599:Cytoskeleton / Q000187:drug effects* / Q000378:metabolism; D005419:Flavonoids / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism; D006710:Homocysteine / Q000494:pharmacology*; D007295:Inositol Phosphates / Q000378:metabolism; D007382:Intermediate Filaments / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D008954:Models, Biological; D010766:Phosphorylation / Q000187:drug effects; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D019311:Staurosporine / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology; D010738:Type C Phospholipases / Q000378:metabolism; D000096926:Benzenesulfonamides
chemical_list: D001596:Benzylamines; D002118:Calcium; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D000242:Cyclic AMP; D005419:Flavonoids; D006710:Homocysteine; D007295:Inositol Phosphates; D020928:Mitogen-Activated Protein Kinases; D011493:Protein Kinase C; D016194:Receptors, N-Methyl-D-Aspartate; D019837:Ryanodine Receptor Calcium Release Channel; D019311:Staurosporine; D013449:Sulfonamides; D010738:Type C Phospholipases; C072105:KN 93; D000096926:Benzenesulfonamides; C052128:inositol 3-phosphate; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one