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

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, GSK3β and FOXO3a. The inhibitory effect of glutamate (1 mm) was blocked by antagonists of the N-methyl-d-aspartate (NMDA) receptor, including MK801 (20 μm) and AP5 (100 μm), 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. 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, GSK3β and FOXO3a. The inhibitory effect of glutamate (1 mm) was blocked by antagonists of the N-methyl-d-aspartate (NMDA) receptor, including MK801 (20 μm) and AP5 (100 μm), 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. Insulin-like growth factor-1 (IGF-1) 2The abbreviations used are: IGF-1, insulin-like growth factor-1; IGF-1R, insulin-like growth factor-1 receptor; AMPA, α-amino-3-hydroxy-5-methy1-4-isoxazoxazolepropionate; IRS-1, insulin receptor substrate-1; MAPK or ERK, mitogen-activated protein kinase; NMDA, N-methyl-d-aspartate; PDK1, phosphatidylinositol 3,4,5-triphosphate-dependent kinase 1; PDK2, phosphatidylinositol 3,4,5-triphosphate-dependent kinase 2; PI3K, phosphatidylinositol 3-kinase; PKC, protein kinase C; GSK3β, glycogen synthase kinase 3β; MEK, MAPK/ERK kinase; mGlu, metabotropic receptor; CPCCOEt, 7-hydroxyiminocyclopropan [b] chromen-1a-carboxylic acid ethyl ester; DNQX, 6,7-Dinitroquinoxaline-2,3-dione. is a trophic factor with multiple biological functions, including important roles during development, and in the maintenance of cellular integrity throughout the organism (1Butler A.A. Yakar S. Gewolb I.H. Karas M. Okubo Y. LeRoith D. Comp. Biochem. Physiol. B Biochem. Mol. 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Glutamate is the major excitatory neurotransmitter in the mammalian brain, responsible for basal excitatory synaptic transmission and many forms of synaptic plasticity such as long term potentiation and long term depression associated with cognitive processes. The various effects of glutamate are mediated by specific receptors belonging to two major families, namely ionotropic and metabotropic receptors (24Beal M.F. FASEB J. 1992; 6 (review): 3338-3344Crossref PubMed Scopus (379) Google Scholar, 25Mark L.P. Prost R.W. Ulmer J.L. Smith M.M. Daniels D.L. Strottmann J.M. Brown W.D. Hacein-Bey L. Am. J. Neuroradiol. 2001; 22 (review): 1813-1824PubMed Google Scholar). Ionotropic glutamate receptors are ligand-gated ion channels consisting of three subtypes known as AMPA(α-amino-3-hydroxy-5-methy1-4-isoxazoxazole propionate), NMDA (N-methyl-d-aspartate), and kainate receptors on the basis of the affinity of their preferential agonist (24Beal M.F. FASEB J. 1992; 6 (review): 3338-3344Crossref PubMed Scopus (379) Google Scholar, 25Mark L.P. Prost R.W. Ulmer J.L. Smith M.M. Daniels D.L. Strottmann J.M. Brown W.D. Hacein-Bey L. Am. J. Neuroradiol. 2001; 22 (review): 1813-1824PubMed Google Scholar). Metabotropic (mGlu) receptors are G-protein-coupled receptors divided into three main classes. Group I mGlu receptors are coupled to phospholipase C and intracellular Ca2+ signaling, whereas group II and III receptors are negatively coupled to adenylyl cyclase and the production of cAMP. Preferential metabotropic receptor agonists include the excitatory amino acid analogue l-quisqualic acid (group I), DCG-IV (group II), and l-AP4 (group III). Glutamate receptors are essential for the normal functioning of the brain. However, their excessive activation can lead to neuronal damage ranging from acute hypoxic-ischemic brain injuries to chronic neurodegenerative diseases (24Beal M.F. FASEB J. 1992; 6 (review): 3338-3344Crossref PubMed Scopus (379) Google Scholar, 25Mark L.P. Prost R.W. Ulmer J.L. Smith M.M. Daniels D.L. Strottmann J.M. Brown W.D. Hacein-Bey L. Am. J. Neuroradiol. 2001; 22 (review): 1813-1824PubMed Google Scholar). Interestingly, it has been suggested that excessive glutamate levels can block the activation of Akt, and hence alter cell survival, linking glutamate excitotoxicity to impaired cell survival signaling (26Chalecka-Franaszek E. Chuang D.M. Proc. Natl. Acad. Sci. U. S. A. 1999; 96: 8745-8750Crossref PubMed Scopus (501) Google Scholar). However, it is not clear from this earlier study if trophic factor signaling pathways are involved. We report here that glutamate is able to attenuate the survival promoting effects of IGF-1 by interrupting IGF-1R survival signaling. The effect of glutamate is mediated by the NMDA receptor sub-type as mimicked by NMDA itself and blocked by an antagonist, MK-801. Taken together, these data reveal a novel mechanism by which glutamate and NMDA receptors regulating trophic factor signaling may be involved in a variety of neurotoxic events leading to neurodegenerative diseases. Materials—Human recombinant IGF-1 was obtained as a gift from Genentech Inc. (San Francisco, CA). Anti-rat C-terminal IRS-1, anti-PI3K p85, and anti-phosphotyrosine (4G10) were purchased from Upstate Biotechnology Inc (Lake Placid, NY); Anti-phospho-IGF-IR (1165/1166), Anti-phospho-IGF-IR (1161), Anti-IGF-IR (1165/1166), Anti-IGF-IR (1161), anti-phospho-SHP-2 (Tyr542), anti-phospho-SHP-2 (Tyr580), anti-SHP-2 (Tyr580), anti-SHP-2 (Tyr542), anti-phospho-Akt-Ser308 were obtained from Signalway (Pearland, TX) via Seaject Scientific (Beijing, and were from Cell and were purchased from Upstate Biotechnology (Lake was from anti-phosphotyrosine and with were from Biotechnology CA). DNQX, NMDA, and 7-hydroxyiminocyclopropan [b] chromen-1a-carboxylic acid ethyl were from were purchased from was from for were purchased from Glutamate and cell were purchased from whereas other were from or cultured neurons were as by W.H. Quirion R. J. Neurochem. PubMed Scopus Google Scholar) with and from of was to and by and the for were in and with and were and or with and to an enzymatic with in for The was by the of concentration and was with to The cellular was obtained by a a for the was and were in a with and were of in with and with the following the the was with was with the as or with were on the the was with the study the signaling pathways induced by IGF-1 in cultured hippocampal were with IGF-1 for study the effect of neurons were for with various of glutamate or NMDA to IGF-1 as were to MK801 (20 and (100 by a with glutamate and with were three to of with and for by hippocampal neurons from were as and the of and its was by with to the was as earlier with (2Zheng W.H. Kar S. Dore S. Quirion R. J. Neural. Transm. Suppl. 2000; 60: 261-272PubMed Google Scholar, W.H. Quirion R. J. Neurochem. PubMed Scopus Google Scholar). from different were with and in and or with of protein were by and the proteins were to were with and in and for and with The were with and with for were several with to and the of the was with to the of of proteins. The phosphorylation of and was by were subsequently and with for protein or to protein of of IGF-1 IRS-1, Shc, and by hippocampal neurons were as that to IGF-1 was were with and for cell were on in for Cell were for and the concentration of protein in was the with as The with of protein was with or anti-PI3K were by protein by and tyrosine phosphorylation was by a of anti-phosphotyrosine and were and with to protein of IGF-1R with NMDA receptors was by of IGF-1 and NMDA receptors and receptor as (2Zheng W.H. Kar S. Dore S. Quirion R. J. Neural. Transm. Suppl. 2000; 60: 261-272PubMed Google Scholar). was not are as of with a was used to between and was Glutamate the of IGF-1 by IGF-1 and in IGF-1 intracellular signaling and excess glutamate have been suggested to be involved in neurodegenerative processes (24Beal M.F. FASEB J. 1992; 6 (review): 3338-3344Crossref PubMed Scopus (379) Google Scholar). the effects of to glutamate on IGF-1R signaling and its survival cultured hippocampal neurons were with and the tyrosine phosphorylation of and the survival effects of IGF-1 were IGF-1 the tyrosine phosphorylation of IGF-1R and and cultured hippocampal neurons from cell Pretreatment with glutamate (1 mm) the tyrosine phosphorylation of and and the survival effects of IGF-1 Glutamate of IRS-1, Shc, and the effect of glutamate on IGF-1R downstream signaling. that glutamate blocked the phosphorylation of and IRS-1, two main proteins of the IGF-1R and that of PI3K, a main downstream signaling protein of IGF-1 the effect of glutamate in the tyrosine phosphorylation of the IGF-1R and its protein was Glutamate of the the of have that the is essential for the survival effects of IGF-1, whereas the MAPK a role W.H. Quirion R. J. Neurochem. PubMed Scopus Google Scholar, W.H. Kar S. Quirion R. Mol. PubMed Scopus Google Scholar). we the effect of a with glutamate on activation of the and MAPK Consistent with results in that a with glutamate (1 mm) the tyrosine phosphorylation of PI3K, it also inhibited the activation of upstream kinase of the phosphorylation of both Thr-308 and Ser-473 of Akt, and the phosphorylation of GSK3β and In the treatment activation of MAPK and its upstream kinase Glutamate (1 by a effect on the Akt the phosphorylation of and MAPK In to Akt and MAPK pathways, a with glutamate (1 mm) also the activation of different of PKC, including and and a effect on kinase receptor antagonists block the effect of glutamate on the tyrosine phosphorylation of the IGF-1R and the pathway. hippocampal neurons were with the NMDA receptor antagonists MK801 or NMDA receptor or for the receptor, AMPA, and kainate and and the effect of glutamate (1 mm) on IGF-1R phosphorylation and the was the NMDA receptor antagonists MK801 and inhibited the effects of glutamate MK801 also the effect of glutamate on the activation of induced by IGF-1 of three The of Glutamate on IGF-1 by the NMDA that glutamate is able to attenuate the signaling survival we the role of various glutamate receptor sub-types on this hippocampal neurons were with the NMDA receptor antagonists MK801 or for the and kainate and and the effect of glutamate (1 mm) on IGF-1R phosphorylation and signaling was MK801 (20 μm), a NMDA receptor antagonist, inhibited the effect of whereas a also blocked it but to a In a concentration (20 μm) known to block effect The metabotropic glutamate receptor subtypes antagonists and also effect on the inhibitory effect of glutamate on IGF-1 signaling not Consistent with the role of NMDA receptor on the effect of glutamate on IGF-1R signaling, that glutamate attenuates phosphorylation of Akt and its downstream targets GSK3β and whereas of hippocampal cultured neurons with this NMDA receptor the effect of antagonists of receptors and metabotropic glutamate receptors effect NMDA the of IGF-1 in further the role of the NMDA receptor the effect of NMDA itself was on receptor signaling. that NMDA (1 mm) the phosphorylation of the IGF-1R and its downstream signaling including MK801 the of Glutamate and NMDA on the of effect of on the inhibitory of glutamate and NMDA on cell survival was (20 μm) blocked the inhibitory effect of glutamate mm) and NMDA (1 mm) on cell survival Glutamate the of the the of was recently that the activation of the tyrosine is able to G. W. A. J. PubMed Scopus Google Scholar). We the role of on the of glutamate on IGF-1R signaling. that glutamate is able to dependently the phosphorylation and activation of the tyrosine the effect of glutamate on the phosphorylation of Akt and IGF-1R for the of Glutamate in further the role of hippocampal neurons were with a of for that for inhibited the of and the effect of glutamate on the phosphorylation of In the present study, we that not is able to attenuate the survival effects of Glutamate by IGF-1R and signaling to the promoting IGF-1 on the MAPK pathway. The effects of glutamate are mediated by the NMDA receptor Glutamate the of IGF-1 in survival effect of IGF-1 was by a treatment with glutamate as as such by effect on cell survival that its effects were not to excitotoxicity but to the of the survival properties of Our data also suggest that cell such as are not able to pathways leading to cell but can also survival pathways hence their findings have been from group E. C. S. 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This hypothesis is on the following concentration dependently inhibited the tyrosine phosphorylation of the IGF-1R and of its protein glutamate the phosphorylation of PI3K and upstream kinase of leading to Akt via This results in the activation of such as by their the glutamate treatment preferentially affected the the MAPK pathway. a to glutamate can reduce IGF-1 survival effect by IGF-1R phosphorylation and Consistent with a report that glutamate was able to the tyrosine in which the of with leading to the of the phosphorylation of this receptor and trophic properties G. W. A. J. PubMed Scopus Google Scholar). In with these data also that glutamate is able to attenuate the phosphorylation of Akt induced by factor in hippocampal neurons. and R. NMDA the of Glutamate on IGF-1 and antagonists of the various glutamate receptors were used to which was responsible for the effects of glutamate on IGF-1R signaling and Our data demonstrate that the NMDA receptor a key the NMDA receptor antagonists MK801 and inhibited the effects of glutamate on the tyrosine phosphorylation of the IGF-1R and its downstream signaling the specific NMDA, concentration dependently mimicked the effect of Taken together, these data show that the NMDA receptor sub-type is involved in the of glutamate on IGF-1R signaling and cell The or underlying the effect of NMDA receptor activation on IGF-1R signaling and cell survival are not NMDA and not with other as various NMDA and IGF-1R to reveal not glutamate on NMDA receptors activates downstream signaling that residues on leading to receptor tyrosine phosphorylation R. A. R. M. Mol. 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The phosphorylation of promotes the of to the IGF-1R leading to receptor D.R. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). Interestingly, lead to the of the and signaling G. W. A. J. PubMed Scopus Google Scholar). This hypothesis is supported by the following glutamate the phosphorylation of the of by the inhibitory effect of glutamate on the phosphorylation of IGF-1R induced by and the tyrosine blocked the effect of glutamate on phosphorylation of IGF-1R and In the present study that via the NMDA receptor is of IGF-1R signaling and survival effects in hippocampal neurons. These findings suggest a novel mechanism by which glutamate can neuronal viability by trophic factor receptor signaling.

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