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N-Methyl-d-aspartate Inhibits Apoptosis through Activation of Phosphatidylinositol 3-Kinase in Cerebellar Granule Neurons

A ROLE FOR INSULIN RECEPTOR SUBSTRATE-1 IN THE NEUROTROPHIC ACTION OF N-METHYL-d-ASPARTATE AND ITS INHIBITION BY ETHANOL*
  • Frank X. Zhang
    Affiliations
    Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, Pennsylvania 19107
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  • Raphael Rubin
    Affiliations
    Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, Pennsylvania 19107
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  • Thomas A. Rooney
    Correspondence
    To whom correspondence should be addressed: Dept. of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, 1020 Locust St., Philadelphia, PA 19107. Tel.: 215-503-1032; Fax: 215-923-2218;
    Affiliations
    Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, Pennsylvania 19107
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  • Author Footnotes
    * This study was funded by National Institutes of Health Grants AA10413 (to T. A. R.), AA09976 and K02 AA123 (to R. R.), and AA07186.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Open AccessPublished:October 09, 1998DOI:https://doi.org/10.1074/jbc.273.41.26596
      Primary cultured rat cerebellar granule neurons underwent apoptosis when switched from medium containing 25 mm K+ to one containing 5 mmK+. N-methyl-d-aspartate (NMDA) protected granule neurons from apoptosis in medium containing 5 mm K+. Inhibition of apoptosis by NMDA was blocked by the phosphatidylinositol 3-kinase (PI 3-kinase) inhibitor LY294002, but it was unaffected by the mitogen-activated protein kinase kinase inhibitor PD 98059. The antiapoptotic action of NMDA was associated with an increase in the tyrosine phosphorylation of insulin receptor substrate 1 (IRS-1), an increase in the binding of the regulatory subunit of PI 3-kinase to IRS-1, and a stimulation of PI 3-kinase activity. In the absence of extracellular Ca2+, NMDA was unable to prevent apoptosis or to phosphorylate IRS-1 and activate PI 3-kinase. Significant inhibition of NMDA-mediated neuronal survival by ethanol (10–15%) was observed at 1 mm, and inhibition was half-maximal at 45–50 mm. Inhibition of neuronal survival by ethanol corresponded with a marked reduction in the capacity of NMDA to increase the concentration of intracellular Ca2+, phosphorylate IRS-1, and activate PI 3-kinase. These data demonstrate that the neurotrophic action of NMDA and its inhibition by ethanol are mediated by alterations in the activity of a PI 3-kinase-dependent antiapoptotic signaling pathway.
      NMDA
      N-methyl-d-aspartate
      PI 3-kinase
      phosphatidylinositol 3-kinase
      BME
      basal medium Eagle
      HK
      high K+
      IGF
      insulin-like growth factor
      IRS-1
      insulin receptor substrate 1
      LK
      low K+
      MK-801
      (+)-5-methyl-10,11-dihydro-5H-dibenzo[a, d]cyclohepten-5,10-imine hydrogen maleate
      MTT
      3-(4,5-dimethyl thiazol-2-yl)-2,5-diphenyl tetrazolium bromide.
      Glutamate functions as the major excitatory neurotransmitter in the mammalian central nervous system by activating ionotropic and metabotropic glutamate receptors (
      • Barnard E.A.
      ,
      • Conn P.J.
      • Pin J.P.
      ). The NMDA1 receptor is an important subtype of ionotropic glutamate receptors that functions as a ligand-gated ion channel and initiates cation influx upon activation by glutamate or NMDA (
      • Sucher N.J.
      • Awobuluyi M.
      • Choi Y.B.
      • Lipton S.A.
      ,
      • McBain C.J.
      • Mayer M.L.
      ). Activated NMDA receptors are about 10 times more permeable to Ca2+ than to Na+ and contain regulatory sites for Mg2+, Zn2+, glycine, polyamines, and phencyclidine (
      • Sucher N.J.
      • Awobuluyi M.
      • Choi Y.B.
      • Lipton S.A.
      ,
      • McBain C.J.
      • Mayer M.L.
      ). An increase in [Ca2+]i is central to many of the properties of NMDA receptor activation in the central nervous system, including its role in development, neuroplasticity, and neurotoxicity (
      • McBain C.J.
      • Mayer M.L.
      ,
      • McDonald J.W.
      • Johnston M.V.
      ).
      NMDA receptors can produce neurotrophic and/or neurotoxic effects in brain, depending on the stage of development and the degree of receptor activation. During restricted developmental periods, NMDA receptor activation has been shown to be important for maintaining neuronal survival, synaptogenesis, synaptic plasticity, learning, and memory (
      • McDonald J.W.
      • Johnston M.V.
      ,
      • Nakanishi S.
      • Masu M.
      ). However, excessive NMDA receptor activation can result in neuronal damage and cell death (
      • Choi D.W.
      ). Recent studies have shown that glutamate-induced cell death in cerebellar granule neurons is composed of sequential necrosis and apoptosis (
      • Ankarcrona M.
      • Dypbukt J.M.
      • Bonfoco E.
      • Zhivotovsky B.
      • Orrenius S.
      • Lipton S.A.
      • Nicotera P.
      ). After exposure to glutamate, a subpopulation of granule neurons undergoes rapid necrotic cell killing that is associated with a loss of mitochondrial function. Neurons surviving the early necrotic phase recover their mitochondrial potential and energy levels and sustain delayed apoptotic cell death. Glutamate-induced apoptosis has been shown to involve a Ca2+-dependent activation of p38 mitogen-activated protein kinase in cerebellar granule neurons (
      • Kawasaki H.
      • Morooka T.
      • Shimohama S.
      • Kimura J.
      • Hirano T.
      • Gotoh Y.
      • Nishida E.
      ).
      In contrast with the excitotoxic effects of high concentrations of NMDA, low doses of NMDA enhance the survival of cerebellar granule neurons (
      • Gallo V.
      • Kingsbury A.
      • Balázs R.
      • Jõrgensen O.S.
      ,
      • Balázs R.
      • Hack N.
      • Resink A.
      • Aronica E.
      • van der Valk J.B.F.
      ). NMDA promotes the survival of cerebellar granule neurons cultured in the presence of physiological [K+] (5 mm) by inhibiting apoptosis (
      • Yan G.-M.
      • Ni B.
      • Weller M.
      • Wood K.A.
      • Paul S.M.
      ). The trophic effects of NMDA in cultured cerebellar granule neurons have been proposed to mimic the ability of glutamatergic innervation in vivo to prevent elimination of postmigratory granule neurons after the formation of synaptic contacts (
      • Yan G.-M.
      • Ni B.
      • Weller M.
      • Wood K.A.
      • Paul S.M.
      ). The mechanism underlying the antiapoptotic action of NMDA in cerebellar granule neurons is unknown.
      The sedative properties of ethanol have led to investigation of its effect on NMDA receptor function. Acute ethanol exposure causes decreases in NMDA-activated ion currents in hippocampal neurons (
      • Lovinger D.M.
      • White G.
      • Weight F.F.
      ), NMDA-induced [Ca2+]i responses, and cGMP production in cerebellar granule neurons (
      • Hoffman P.L.
      • Rabe C.S.
      • Moses F.
      • Tabakoff B.
      ), and NMDA-evoked neurotransmitter release in rat brain slices (
      • Woodward J.J.
      • Gonzales R.A.
      ). Prenatal ethanol exposure decreases NMDA-sensitive [3H]glutamate receptor binding (
      • Farr K.L.
      • Montano C.Y.
      • Paxton L.L.
      • Savage D.D.
      ) and functional responses to NMDA and metabotropic glutamate receptors (
      • Morrisett R.A.
      • Martin D.
      • Wilson W.A.
      • Savage D.D.
      • Swartzwelder H.S.
      ,
      • Queen S.A.
      • Sanchez C.F.
      • Lopez S.R.
      • Paxton L.L.
      • Savage D.D.
      ) in rat hippocampus. In cerebellar granule neurons, both the neurotrophic (
      • Wegelius K.
      • Korpi E.R.
      ,
      • Bhave S.V.
      • Hoffman P.L.
      ) and excitotoxic (
      • Wegelius K.
      • Korpi E.R.
      ) actions of NMDA are inhibited by ethanol. Further studies have indicated that NMDA receptor activation can protect against ethanol-induced cell death in newly established cultures of cerebellar granule neurons (
      • Pantazis N.J.
      • Dohrman D.P.
      • Luo J.
      • Thomas J.D.
      • Goodlett C.R.
      • West J.R.
      ).
      We have recently demonstrated that ethanol can also induce apoptosis by inhibiting IGF-I signaling in cerebellar granule neurons (
      • Zhang F.X.
      • Rubin R.
      • Rooney T.A.
      ). Ethanol blocks the antiapoptotic action of IGF-I by inhibiting its ability to promote IRS-1 phosphorylation and stimulate PI 3-kinase. Inhibition of IGF-I signaling by ethanol occurs downstream of the ligand binding site (
      • Zhang F.X.
      • Rubin R.
      • Rooney T.A.
      ,
      • Resnicoff M.
      • Sell C.
      • Ambrose D.
      • Baserga R.
      • Rubin R.
      ) and is mediated by blocking IGF-I receptor autophosphorylation (
      • Resnicoff M.
      • Sell C.
      • Ambrose D.
      • Baserga R.
      • Rubin R.
      ). Ethanol also inhibits IGF-I-induced cell proliferation in Balb/c 3T3 cells (
      • Resnicoff M.
      • Sell C.
      • Ambrose D.
      • Baserga R.
      • Rubin R.
      ) and IGF-I- and IGF-2-mediated cell growth in C6 rat glioblastoma cells (
      • Resnicoff M.
      • Rubini M.
      • Baserga R.
      • Rubin R.
      ). Inhibition of cell growth by ethanol in C6 glioblastoma cells is accompanied by a block of IRS-1 phosphorylation and PI-3 kinase activation (
      • Resnicoff M.
      • Rubini M.
      • Baserga R.
      • Rubin R.
      ).
      In the present study, we have examined the mechanism by which NMDA promotes neuronal survival in cerebellar granule neurons and the involvement of these processes in the neurotoxic action of ethanol. Our data show that the ability of NMDA to inhibit apoptosis in cerebellar granule neurons is associated with a Ca2+-dependent increase in the tyrosine phosphorylation of IRS-1, the binding of PI 3-kinase to IRS-1, and the activation of PI 3-kinase. Ethanol inhibits NMDA-induced [Ca2+]i increases and blocks the capacity of NMDA to protect cerebellar granule neurons from apoptotic cell death. Inhibition of NMDA-mediated neuronal survival by ethanol also corresponds with a marked reduction in the phosphorylation of IRS-1, the binding of PI 3-kinase to IRS-1, and the activation of PI 3-kinase. These data demonstrate that NMDA prevents apoptosis through activation of PI 3-kinase and that ethanol induces cell death in cerebellar granule neurons by inhibiting NMDA-induced activation of a PI 3-kinase-dependent antiapoptotic signaling pathway.

      DISCUSSION

      In the present study, we have shown that NMDA inhibits LK-induced apoptosis in cerebellar granule neurons through the activation of PI 3-kinase. Activation of PI 3-kinase by NMDA depends on the stimulation of Ca2+ entry and is associated with an increase in the tyrosine phosphorylation of IRS-1 and the binding of PI 3-kinase to IRS-1. Ethanol significantly inhibits the ability of NMDA to increase [Ca2+]i and blocks its capacity to protect cerebellar granule neurons from apoptotic cell death. Inhibition of NMDA-mediated neuronal survival by ethanol also corresponds with a marked reduction in NMDA-stimulated IRS-1 phosphorylation and NMDA-induced PI 3-kinase activity. These findings demonstrate that the antiapoptotic action of NMDA (and its inhibition by ethanol) involves cross-talk with the IGF-I signaling pathway.
      Ca2+ entry has been shown to play an important role in the neurotrophic action of NMDA in cerebellar granule neurons (
      • Balázs R.
      • Hack N.
      • Resink A.
      • Aronica E.
      • van der Valk J.B.F.
      ). Inhibition of NMDA-mediated Ca2+ entry has also been proposed to contribute to ethanol neurotoxicity because ethanol inhibits the trophic effect of NMDA and NMDA-induced [Ca2+]i increases with similar potency (
      • Bhave S.V.
      • Hoffman P.L.
      ). However, little is known about the downstream signaling pathways responsible for the Ca2+-dependent neurotrophic action of NMDA and their potential to serve as targets for the neurotoxic action of ethanol. Some data have suggested that promotion of neuronal survival by NMDA and HK in cerebellar granule neurons involves activation of Ca2+/calmodulin-dependent protein kinase (
      • Hack N.
      • Hidaka H.
      • Wakefield M.J.
      • Balázs R.
      ) or release of a parathyroid hormone-related protein (
      • Ono T.
      • Inokuchi K.
      • Ogura A.
      • Ikawa Y.
      • Kudo Y.
      • Kawashima S.
      ). Expression of parathyroid hormone/parathyroid hormone-related protein receptor mRNA is also up-regulated in an activity-dependent manner by NMDA and HK (
      • Ono T.
      • Inokuchi K.
      • Ogura A.
      • Ikawa Y.
      • Kudo Y.
      • Kawashima S.
      ). There have also been inconsistent findings pertaining to the role of PI 3-kinase in HK-mediated neuronal survival in cerebellar granule neurons, with one study indicating a requirement for PI 3-kinase activation (
      • Miller T.M.
      • Tansey M.G.
      • Johnson Jr., E.M.
      • Creedon D.J.
      ), whereas another showed that the neurotrophic action of HK does not involve activation of PI 3-kinase (
      • D'Mello S.R.
      • Borodezt K.
      • Soltoff S.P.
      ).
      Our data show that the ability of NMDA-stimulated Ca2+entry to inhibit apoptosis depends on the activation of PI 3-kinase and is associated with the phosphorylation of IRS-1. We have recently shown that ethanol does not inhibit HK-induced neuronal survival in cerebellar granule neurons, under conditions where it blocks the antiapoptotic action of IGF-I by inhibiting its ability to promote IRS-1 phosphorylation and stimulate PI 3-kinase (
      • Zhang F.X.
      • Rubin R.
      • Rooney T.A.
      ). Previous studies have established that inhibition of IGF-I signaling by ethanol occurs distal from the ligand binding interaction (
      • Zhang F.X.
      • Rubin R.
      • Rooney T.A.
      ,
      • Resnicoff M.
      • Sell C.
      • Ambrose D.
      • Baserga R.
      • Rubin R.
      ) and is mediated by blocking IGF-I receptor autophosphorylation (
      • Resnicoff M.
      • Sell C.
      • Ambrose D.
      • Baserga R.
      • Rubin R.
      ). This indicates that ethanol can induce apoptosis by inhibiting individual components of distinct signaling pathways and blocking their capacity to activate PI 3-kinase.
      IRS-1 is one of the major substrates phosphorylated in response to stimulation by insulin or IGF-I, and it functions as a docking protein that associates with and activates several Src homology 2 domain-containing proteins, including PI 3-kinase (
      • LeRoith D.
      • Werner H.
      • Beitner-Johnson D.
      • Roberts Jr., C.T.
      ,
      • D'Ercole A.J.
      • Ye P.
      • Calikoglu A.S.
      • Gutierrez-Ospina G.
      ). IRS-1 can be phosphorylated in response to a number of other ligands, including tumor necrosis factor (
      • Guo D.
      • Donner D.
      ), brain-derived neurotrophic factor (
      • Yamada M.
      • Ohnishi H.
      • Sano S.
      • Nakatani A.
      • Ikeuchi T.
      • Hatanaka H.
      ), interleukin-4, oncostatin M, and the interferons (
      • Burfoot M.S.
      • Rogers N.C.
      • Watling D.
      • Smith J.M.
      • Pons S.
      • Paonessaw G.
      • Pellegrini S.
      • White M.F.
      • Kerr I.M.
      ). The results of the present study demonstrate that phosphorylation of IRS-1 and the association of PI 3-kinase with IRS-1 can also be stimulated by the increase in [Ca2+]i following activation of the NMDA receptor. Although the mechanism through which elevated [Ca2+]i stimulates tyrosine phosphorylation of IRS-1 remains to be established, several intracellular proteins are capable of mediating cross-talk between NMDA and IRS-1-linked signaling pathways. For example, Ca2+ influx increases the activity of the tyrosine kinases PYK2 (
      • Lev S.
      • Moreno H.
      • Martinez R.
      • Canoll P.
      • Peles E.
      • Musacchio J.M.
      • Plowman G.D.
      • Rudy B.
      • Schlessinger J.
      ) and Src (
      • Rusanescu G.
      • Qi H.
      • Thomas S.M.
      • Brugge J.S.
      • Halegoua S.
      ) in PC12 cells. Src kinase induces ligand-independent phosphorylation and activation of the IGF-I receptor in rat fibroblasts (
      • Peterson J.E.
      • Jelink T.
      • Kaleko M.
      • Siddle K.
      • Weber M.J.
      ,
      • Peterson J.E.
      • Kulik G.
      • Jelinek T.
      • Reuter C.W.M.
      • Shannon J.A.
      • Weber M.J.
      ), and it physically associates with NMDA receptors and increases NMDA channel activity in spinal dorsal horn neurons (
      • Yu X.-M.
      • Askalan R.
      • Keil G.J.
      • Salter M.W.
      ). Additional reports have shown that calmodulin binds to IRS-1 (
      • Munshi H.G.
      • Burks D.J.
      • Joyal J.L.
      • White M.F.
      • Sacks D.B.
      ) and the p85 regulatory subunit of PI 3-kinase (
      • Joyal J.L.
      • Burks D.J.
      • Pons S.
      • Matter W.F.
      • Vlahos C.J.
      • White M.F.
      • Sacks D.B.
      ) in Chinese hamster ovary cell lysates and activates PI 3-kinase in a Ca2+-dependent manner in intact Chinese hamster ovary cells (
      • Joyal J.L.
      • Burks D.J.
      • Pons S.
      • Matter W.F.
      • Vlahos C.J.
      • White M.F.
      • Sacks D.B.
      ).
      Fyn tyrosine kinase may also provide a link between components of these two signaling pathways and contribute to ethanol sensitivity by modulating the function of receptors that are targets of ethanol action. Thus, Fyn kinase binds and phosphorylates IRS-1 (
      • Sun X.J.
      • Pons S.
      • Asano T.
      • Myers Jr., M.G.
      • Glasheen E.
      • White M.F.
      ) and regulates behavioral sensitivity to ethanol and the ability of ethanol to interfere with NMDA receptor function (
      • Miyakawa T.
      • Yagi T.
      • Kitazawa H.
      • Yasuda M.
      • Kawai N.
      • Tsuboi K.
      • Niki H.
      ). Fyn-deficient mice have been shown to be more sensitive to the hypnotic effect of ethanol and do not exhibit enhanced tyrosine phosphorylation of the NMDA receptor after ethanol treatment (
      • Miyakawa T.
      • Yagi T.
      • Kitazawa H.
      • Yasuda M.
      • Kawai N.
      • Tsuboi K.
      • Niki H.
      ). In addition, acute tolerance to ethanol inhibition of NMDA-mediated excitatory postsynaptic potentials is not observed in hippocampal slices from mice lacking Fyn kinase.
      NMDA-induced neuronal survival was inhibited by LY294002 but unaffected by PD98509. This is consistent with previous studies of the neurotrophic action of IGF-I in cerebellar granule neurons (
      • Zhang F.X.
      • Rubin R.
      • Rooney T.A.
      ,
      • Miller T.M.
      • Tansey M.G.
      • Johnson Jr., E.M.
      • Creedon D.J.
      ,
      • D'Mello S.R.
      • Borodezt K.
      • Soltoff S.P.
      ) and indicates that the antiapoptotic response of NMDA requires activation of PI 3-kinase and is independent of mitogen-activated protein kinase kinase. The signaling pathways through which PI 3-kinase activation promotes neuronal survival have recently started to be elucidated. For example, studies have shown that the serine-threonine protein kinase Akt (protein kinase B) is an important mediator of PI 3-kinase-dependent neuronal survival (
      • Dudek H.
      • Datta S.R.
      • Franke T.F.
      • Birnbaum M.J.
      • Yao R.
      • Cooper G.M.
      • Segal R.A.
      • Kaplan D.R.
      • Greenberg M.E.
      ). The lipid products of PI 3-kinase bind to Akt and promote membrane translocation (
      • Franke T.F.
      • Kaplan D.R.
      • Cantley L.C.
      • Toker A.
      ), thereby enabling its phosphorylation and activation by a recently identified family of Akt kinases (
      • Stokoe D.
      • Stephens L.R.
      • Copeland T.
      • Gaffney P.R.J.
      • Reese C.B.
      • Painter G.F.
      • Holmes A.B.
      • McCormick F.
      • Hawkins P.T.
      ,
      • Stephens L.R.
      • Anderson K.
      • Stokoe D.
      • Erdjument-Bromage H.
      • Painter G.F.
      • Holmes A.B.
      • Gaffney P.R.J.
      • Reese C.B.
      • McCormick F.
      • Tempst P.
      • Coadwell J.
      • Hawkins P.T.
      ). Activated forms of Akt have been found to phosphorylate BAD (
      • Datta S.R.
      • Dudek H.
      • Tao X.
      • Masters S.
      • Fu H.
      • Gotoh Y.
      • Greenberg M.E.
      ,
      • del Peso L.
      • Gonzalez-Garcia M.
      • Page C.
      • Herrera R.
      • Nunez G.
      ), which leads to its association with 14-3-3 proteins and prevents BAD from binding to and inhibiting the survival proteins Bcl-XL and Bcl-2 (
      • Zha J.
      • Harada H.
      • Yang E.
      • Jockel J.
      • Korsmeyer S.
      ).
      The ability of prenatal ethanol exposure to induce brain damage that can result in severe mental retardation linked to fetal alcohol syndrome, or associated attention disorders and hyperactivity, has been well documented (
      • Jones K.L.
      • Smith D.W.
      ,
      • Marcus J.C.
      ). The cerebellar region of the developing central nervous system is particularly sensitive to ethanol-induced cell injury, with decreases in cerebellar size, the number of granule and Purkinje neurons, and delayed neuronal maturation and synapse formation, all consequences of ethanol exposure (
      • Bauer-Moffett C.
      • Altman J.
      ,
      • Volk B.
      ). However, the mechanisms underlying the teratogenic effects of ethanol in brain have remained ill defined. Most in vitro studies of the effects of ethanol on neuronal survival in cerebellum have assessed cell death by using markers of plasma membrane integrity (
      • Wegelius K.
      • Korpi E.R.
      ,
      • Pantazis N.J.
      • Dohrman D.P.
      • Goodlett C.R.
      • Cook R.T.
      • West J.R.
      ,
      • Zou J.-Y.
      • Cohan C.
      • Rabin R.A.
      • Pentney R.J.
      ). Although these probes provide a measure of cell viability, they do not distinguish between apoptotic and necrotic forms of cell death or define any of the events mediating these two processes. Moreover, there have been contradictory reports concerning the effects of ethanol on neuronal survival, with some indicating that ethanol has a direct neurotoxic action (
      • Pantazis N.J.
      • Dohrman D.P.
      • Goodlett C.R.
      • Cook R.T.
      • West J.R.
      ) and others showing that ethanol acts by inhibiting neurotrophic support (
      • Wegelius K.
      • Korpi E.R.
      ,
      • Bhave S.V.
      • Hoffman P.L.
      ,
      • Zhang F.X.
      • Rubin R.
      • Rooney T.A.
      ). Here, we show that ethanol can induce apoptotic cell death in cerebellar granule neurons by inhibiting the ability of NMDA to activate a PI 3-kinase-dependent neuronal survival pathway.
      In conclusion, the data presented here demonstrate that the ability of NMDA to inhibit apoptosis in cerebellar granule neurons is mediated by a Ca2+-dependent activation of PI 3-kinase. The activation of PI 3-kinase by NMDA is associated with an increase in both the phosphorylation of IRS-1 and the binding of PI 3-kinase to IRS-1. Ethanol blocks the antiapoptotic action of NMDA and inhibits NMDA-mediated [Ca2+]i increases, IRS-1 phosphorylation, and PI 3-kinase activation. These findings describe a new role for PI 3-kinase and IRS-1 in NMDA signaling and reveal an additional mechanism whereby ethanol induces apoptosis in cerebellar granule neurons by inhibiting NMDA-induced PI 3-kinase activation.

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