Group I metabotropic receptor neuroprotection requires Akt and its substrates that govern FOXO3a, Bim, and beta-catenin during oxidative stress.
Metabotropic glutamate receptors are expressed throughout the nervous system, but their function as well as their ability to promote neuronal survival rests heavily upon the intracellular mechanisms governed by this family of G-proteins. In this regard, we examined one of the primary pathways that can oversee cell survival, namely protein kinase B (Akt1), and its functional integration with some of its substrates that may work in concert with group I metabotropic glutamate receptor (mGluRI) activation to protect primary hippocampal neurons during oxidative stress. We demonstrate that neuroprotection against free radical injury through mGluRI activation with DHPG requires the activation of Akt1, since loss of Akt1 activity assessed through its GSK-3alpha/beta substrate by pharmacological blockade of the phosphatidylinositide-3-kinase pathway or the gene silencing of Akt1 expression prevents neuronal protection during mGluRI activation. Closely coupled to the robust neuroprotection by mGluRI activation are the inhibitory phosphorylation and prevention of caspase 3 cleavage of the Forkhead transcription factor FOXO3a, the down-regulation of Bim expression, and the protection of beta-catenin by Akt1 against phosphorylation and degradation to promote its translocation from the cytoplasm to the nucleus and allow it to assist with a "pro-survival" cellular program. Further insight into the cellular mechanisms that determine neuronal protection by the metabotropic glutamate system will foster the successful therapeutic development of mGluRs for neurodegenerative disorders.
Chong
Zhao Zhong
ZZ
Division of Cellular and Molecular Cerebral Ischemia, Wayne State University School of Medicine, Detroit, MI 48201, USA.
Li
Faqi
F
Maiese
Kenneth
K
D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D000072224:Bcl-2-Like Protein 11; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D019610:Cytoprotection / Q000187:drug effects / Q000502:physiology; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D005609:Free Radicals / Q000037:antagonists & inhibitors / Q000378:metabolism; D020868:Gene Silencing / Q000187:drug effects / Q000502:physiology; D038362:Glycogen Synthase Kinase 3 / Q000187:drug effects / Q000378:metabolism; D006624:Hippocampus / Q000378:metabolism / Q000503:physiopathology; D008565:Membrane Proteins / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018094:Receptors, Metabotropic Glutamate / Q000378:metabolism*; D012717:Sesquiterpenes / Q000494:pharmacology; D045789:Sesquiterpenes, Guaiane; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D051176:beta Catenin / Q000378:metabolism*
D051017:Apoptosis Regulatory Proteins; D000072224:Bcl-2-Like Protein 11; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D005609:Free Radicals; D038362:Glycogen Synthase Kinase 3; D008565:Membrane Proteins; D019869:Phosphatidylinositol 3-Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D034741:RNA, Small Interfering; D018094:Receptors, Metabotropic Glutamate; D012717:Sesquiterpenes; D045789:Sesquiterpenes, Guaiane; D051176:beta Catenin; C487266:9alpha,10beta-dihydroxy-2beta,4beta-peroxy-1alpha,5beta,7alphaH-guaiane; C000606778:Bcl2l11 protein, rat; C495268:Ctnnb1 protein, rat; C499515:FOXO3 protein, rat; C104077:metabotropic glutamate receptor type 1; C448021:glycogen synthase kinase 3 alpha