Document Detail


Glutamate acting on N-methyl-D-aspartate receptors attenuates insulin-like growth factor-1 receptor tyrosine phosphorylation and its survival signaling properties in rat hippocampal neurons.
MedLine Citation:
PMID:  18981172     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Impairing intracellular signaling induced by survival factors and excess glutamate have recently been suggested to play important role in neurodegenerative processes. However, the underlying mechanism(s) and interrelationships between these factors mostly remain to be established. In the present study, we show that glutamate attenuates the tyrosine phosphorylation of the insulin-like growth factor-1 (IGF-1) receptor and the survival effect of IGF-1 (100 nm) in hippocampal cultured neurons. Pretreatment of cultured hippocampal neurons with glutamate concentration dependently inhibited the tyrosine phosphorylation of IGF-1 receptors as well as that of IRS-1 and Shc, two IGF-1 receptor adapter proteins. The effect of glutamate was also evident on the phosphorylation of Akt, as well as its upstream kinase PI3K/PDK1 and downstream targets, GSK3beta and FOXO3a. The inhibitory effect of glutamate (1 mm) was blocked by antagonists of the N-methyl-d-aspartate (NMDA) receptor, including MK801 (20 microm) and AP5 (100 microm), but not by blockers of other ionotropic or metabotropic glutamate receptor sub-types demonstrating the involvement of the NMDA receptor. This hypothesis is supported further by the observation that treatment with NMDA concentration dependently inhibited the activation and phosphorylation of IGF-1 receptors and downstream targets induced by IGF-1 (100 nm). These findings demonstrate that glutamate can block the effect of IGF-1 by decreasing IGF-1 receptor signaling and responsiveness, hence attenuating the survival properties of this trophic factor in neuronal cells. Our results also suggest a novel mechanism by which glutamate can reduce cell viability and induce neurotoxicity.
Authors:
Wen-Hua Zheng; Rémi Quirion
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2008-11-03
Journal Detail:
Title:  The Journal of biological chemistry     Volume:  284     ISSN:  0021-9258     ISO Abbreviation:  J. Biol. Chem.     Publication Date:  2009 Jan 
Date Detail:
Created Date:  2009-01-05     Completed Date:  2009-03-06     Revised Date:  2009-11-19    
Medline Journal Info:
Nlm Unique ID:  2985121R     Medline TA:  J Biol Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  855-61     Citation Subset:  IM    
Affiliation:
Douglas Mental Health University Institute, Department of Psychiatry, McGill University, Montreal, Quebec H4H 1R3, Canada.
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MeSH Terms
Descriptor/Qualifier:
1-Phosphatidylinositol 3-Kinase / metabolism
Animals
Cell Survival
Enzyme Activation / drug effects
Female
Glutamic Acid / pharmacology*
Hippocampus / cytology,  drug effects*,  metabolism*
Humans
Insulin Receptor Substrate Proteins / metabolism
Insulin-Like Growth Factor I / pharmacology
MAP Kinase Signaling System / drug effects*
Phosphotyrosine / metabolism*
Protein Tyrosine Phosphatase, Non-Receptor Type 11 / genetics,  metabolism
RNA, Small Interfering / genetics
Rats
Rats, Sprague-Dawley
Receptor, IGF Type 1 / metabolism*
Receptors, N-Methyl-D-Aspartate / metabolism*
Shc Signaling Adaptor Proteins / metabolism
Tissue Culture Techniques
Chemical
Reg. No./Substance:
0/Insulin Receptor Substrate Proteins; 0/Irs1 protein, rat; 0/RNA, Small Interfering; 0/Receptors, N-Methyl-D-Aspartate; 0/Shc Signaling Adaptor Proteins; 21820-51-9/Phosphotyrosine; 56-86-0/Glutamic Acid; 67763-96-6/Insulin-Like Growth Factor I; EC 2.7.1.137/1-Phosphatidylinositol 3-Kinase; EC 2.7.10.1/Receptor, IGF Type 1; EC 3.1.3.48/Protein Tyrosine Phosphatase, Non-Receptor Type 11

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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