Phenylalanine inhibition of the phosphorylation of cytoskeletal proteins from cerebral cortex of young rats is prevented by alanine

Carreras,; Mattos‐Dutra, De; Meirelles,; Rocha, Da; Wannmacher,; Pessoa‐Pureur,

doi:10.1046/j.1365-2362.2000.00669.x

Cited by 6 publications

(1 citation statement)

References 31 publications

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“…We have previously demonstrated that the low stoichiometry of IF phosphorylation under basal conditions increases about 30% in rat brain slices exposed to toxic levels of metabolites , or toxins. ,, Conversely, hypophosphorylation has also been observed, reflecting misregulation of the phosphorylating system in response to different signals. − In this context, different concentrations of (PhTe) 2 , from 5 to 100 μM, induced hypophosphorylation of GFAP and NF subunits mediated by activation of protein phosphatase 1 (PP1) in cerebral cortex of 9 and 15 day-old animals . Also, intracellular Ca 2+ levels were identified to be upstream of the signaling pathways targeting the cytoskeleton.…”

Section: Introductionmentioning

confidence: 97%

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

Heimfarth

Loureiro

Reis

et al. 2011

Chem. Res. Toxicol.

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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.

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Section: Introductionmentioning

confidence: 97%

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

Heimfarth

Loureiro

Reis

et al. 2011

Chem. Res. Toxicol.

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Effects of Chronic Photobiomodulation with Transcranial Near-Infrared Laser on Brain Metabolomics of Young and Aged Rats

et al. 2021

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Experimental hyperphenylalaninemia provokes oxidative stress in rat brain

Hagen

Pederzolli

Sgaravatti

et al. 2002

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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Tissue accumulation of L-phenylalanine (Phe) is the biochemical hallmark of human phenylketonuria (PKU), an inherited metabolic disorder clinically characterized by mental retardation and other neurological features. The mechanisms of brain damage observed in this disorder are poorly understood. In the present study we investigated some oxidative stress parameters in the brain of rats with experimental hyperphenylalaninemia. Chemiluminescence, total radical-trapping antioxidant potential (TRAP), superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GSH-Px) activities were measured in the brain of the animals. We observed that chemiluminescence is increased and TRAP is reduced in the brain of hyperphenylalaninemic rats. Similar data were obtained in the in vitro experiments using Phe at various concentrations. CAT activity was significantly inhibited by Phe in vitro and in vivo, whereas GSH-Px activity was reduced in vivo but not in vitro and SOD activity was not altered by any treatment. The results indicate that oxidative stress may be involved in the neuropathology of PKU. However, further studies are necessary to confirm and extend our findings to the human condition and also to determine whether an antioxidant therapy may be of benefit to these patients.

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Phenylalanine inhibition of the phosphorylation of cytoskeletal proteins from cerebral cortex of young rats is prevented by alanine

Abstract: In case the inhibition of cytoskeletal protein phosphorylation by phenylalanine also occurs in human phenylketonuria, it is possible that alanine supplementation to the phenylalanine-restricted diet may be beneficial to these patients.

Cited by 6 publications

References 31 publications

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

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

Effects of Chronic Photobiomodulation with Transcranial Near-Infrared Laser on Brain Metabolomics of Young and Aged Rats

Experimental hyperphenylalaninemia provokes oxidative stress in rat brain

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