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rdf:type |
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lifeskim:mentions |
umls-concept:C0019564,
umls-concept:C0027882,
umls-concept:C0034693,
umls-concept:C0034721,
umls-concept:C0037083,
umls-concept:C0038952,
umls-concept:C0080093,
umls-concept:C0202220,
umls-concept:C0220839,
umls-concept:C0597357,
umls-concept:C0599946,
umls-concept:C0682002,
umls-concept:C0871161,
umls-concept:C1519726,
umls-concept:C1710082
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pubmed:issue |
2
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pubmed:dateCreated |
2009-1-5
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pubmed:abstractText |
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.
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
IM
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pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/Glutamic Acid,
http://linkedlifedata.com/resource/pubmed/chemical/Insulin Receptor Substrate Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Insulin-Like Growth Factor I,
http://linkedlifedata.com/resource/pubmed/chemical/Irs1 protein, rat,
http://linkedlifedata.com/resource/pubmed/chemical/Phosphatidylinositol 3-Kinases,
http://linkedlifedata.com/resource/pubmed/chemical/Phosphotyrosine,
http://linkedlifedata.com/resource/pubmed/chemical/Protein Tyrosine Phosphatase...,
http://linkedlifedata.com/resource/pubmed/chemical/RNA, Small Interfering,
http://linkedlifedata.com/resource/pubmed/chemical/Receptor, IGF Type 1,
http://linkedlifedata.com/resource/pubmed/chemical/Receptors, N-Methyl-D-Aspartate,
http://linkedlifedata.com/resource/pubmed/chemical/Shc Signaling Adaptor Proteins
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pubmed:status |
MEDLINE
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pubmed:month |
Jan
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pubmed:issn |
0021-9258
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pubmed:author |
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pubmed:issnType |
Print
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pubmed:day |
9
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pubmed:volume |
284
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
855-61
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pubmed:dateRevised |
2010-11-18
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pubmed:meshHeading |
pubmed-meshheading:18981172-Animals,
pubmed-meshheading:18981172-Cell Survival,
pubmed-meshheading:18981172-Enzyme Activation,
pubmed-meshheading:18981172-Female,
pubmed-meshheading:18981172-Glutamic Acid,
pubmed-meshheading:18981172-Hippocampus,
pubmed-meshheading:18981172-Humans,
pubmed-meshheading:18981172-Insulin Receptor Substrate Proteins,
pubmed-meshheading:18981172-Insulin-Like Growth Factor I,
pubmed-meshheading:18981172-MAP Kinase Signaling System,
pubmed-meshheading:18981172-Phosphatidylinositol 3-Kinases,
pubmed-meshheading:18981172-Phosphotyrosine,
pubmed-meshheading:18981172-Protein Tyrosine Phosphatase, Non-Receptor Type 11,
pubmed-meshheading:18981172-RNA, Small Interfering,
pubmed-meshheading:18981172-Rats,
pubmed-meshheading:18981172-Rats, Sprague-Dawley,
pubmed-meshheading:18981172-Receptor, IGF Type 1,
pubmed-meshheading:18981172-Receptors, N-Methyl-D-Aspartate,
pubmed-meshheading:18981172-Shc Signaling Adaptor Proteins,
pubmed-meshheading:18981172-Tissue Culture Techniques
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pubmed:year |
2009
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pubmed:articleTitle |
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.
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pubmed:affiliation |
Douglas Mental Health University Institute, Department of Psychiatry, McGill University, Montreal, Quebec H4H 1R3, Canada.
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pubmed:publicationType |
Journal Article,
Research Support, Non-U.S. Gov't
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