Glutamate Receptor Signaling Interplay Modulates Stress-sensitive Mitogen-activated Protein Kinases and Neuronal Cell Death

Glutamate receptors modulate multiple signaling pathways, several of which involve mitogen-activated protein (MAP) kinases, with subsequent physiological or pathological consequences. Here we report that stimulation of theN-methyl-d-aspartate (NMDA) receptor, using platelet-activating factor (PAF) as a messenger, activates MAP kinases, including c-Jun NH2-terminal kinase, p38, and extracellular signal-regulated kinase, in primary cultures of hippocampal neurons. Activation of the metabotropic glutamate receptor (mGluR) blocks this NMDA-signaling through PAF and MAP kinases, and the resultant cell death. Recombinant PAF-acetylhydrolase degrades PAF generated by NMDA-receptor activation; the hetrazepine BN50730 (an intracellular PAF receptor antagonist) also inhibits both NMDA-stimulated MAP kinases and neuronal cell death. The finding that the NMDA receptor-PAF-MAP kinase signaling pathway is attenuated by mGluR activation highlights the exquisite interplay between glutamate receptors in the decision making process between neuronal survival and death. Glutamate receptors modulate multiple signaling pathways, several of which involve mitogen-activated protein (MAP) kinases, with subsequent physiological or pathological consequences. Here we report that stimulation of theN-methyl-d-aspartate (NMDA) receptor, using platelet-activating factor (PAF) as a messenger, activates MAP kinases, including c-Jun NH2-terminal kinase, p38, and extracellular signal-regulated kinase, in primary cultures of hippocampal neurons. Activation of the metabotropic glutamate receptor (mGluR) blocks this NMDA-signaling through PAF and MAP kinases, and the resultant cell death. Recombinant PAF-acetylhydrolase degrades PAF generated by NMDA-receptor activation; the hetrazepine BN50730 (an intracellular PAF receptor antagonist) also inhibits both NMDA-stimulated MAP kinases and neuronal cell death. The finding that the NMDA receptor-PAF-MAP kinase signaling pathway is attenuated by mGluR activation highlights the exquisite interplay between glutamate receptors in the decision making process between neuronal survival and death. Glutamate receptors participate in neural development, plasticity, learning, memory, and pathology, (e.g. excitotoxicity and neurodegenerative diseases.) Overactivation of the glutamate ionotropic receptors leads to excitotoxic cell death. NMDA 1The abbreviations used are: NMDA, N-methyl-d-aspartate; MAP, mitogen-activated protein; PAF, platelet-activating factor; mGluR, metabotropic glutamate receptor; LTP, long-term potentiation; GST, glutathioneS-transferase; DAPI, 4′,6-diamidino-2-phenylindol dihydrochloride; rPAF-AH, recombinant PAF acetylhydrolase; DHPG, (S)-3,5-dihydroxyphenylglycine; HPG, (RS)-3-hydroxyphenylglycine; CPG, S(+)-4-carboxyphenylglycine; JNK, c-Jun NH2-terminal kinase; ERK, extracellular signal-regulated kinase; 1S , 3R-ACPD, (1S,3R)-1-aminocytopentane-1,3-dicarboxylic acid; Ara-C, cytosine arabinoside. receptor antagonism results in prominent neuroprotection in vivo and in vitro. The signals generated by these receptors activate the stress-sensitive MAP kinases JNK and p38 that are implicated in neuronal apoptosis (1Xia Z. Dickens M. Raingeaud J. Davis R.J. Greenberg M.E. Science. 1995; 270: 1326-1331Crossref PubMed Scopus (5074) Google Scholar). A role for JNK in the excitotoxic death of hippocampal neurons in vivo has been recently illustrated using JNK3 −/− mice (2Yang D.D. Kuan C.Y. Whitmarsh A.J. Rincon M. Zheng T.S. Davis R.J. Rakic P. Flavell R.A. Nature. 1997; 389: 865-870Crossref PubMed Scopus (1127) Google Scholar). However, the specific messengers and potential antagonist drugs involved in these signaling pathways are not understood. The bioactive phospholipid, platelet-activating factor (PAF), is a candidate mediator of excitatory amino acid signaling because it is a retrograde messenger of long-term potentiation (LTP) (3Kato K. Clark G.D. Bazan N.G. Zorumski C.F. Nature. 1994; 367: 175-179Crossref PubMed Scopus (225) Google Scholar, 4Wieraszko A. Li G. Kornecki E. Hogan M.V. Ehrlich Y.H. Neuron. 1993; 10: 553-557Abstract Full Text PDF PubMed Scopus (145) Google Scholar) that enhances glutamate release (5Clark G.D. Happel L.T. Zorumski C.F. Bazan N.G. Neuron. 1992; 9: 1211-1216Abstract Full Text PDF PubMed Scopus (189) Google Scholar), is generated by NMDA receptor activation (6Nishida K. Markey S.P. Kustova Y. Mores H.C. Skolnick P. Basile A.S. Sei Y. J. Neurochem. 1996; 66: 433-435Crossref PubMed Scopus (41) Google Scholar), and participates in memory formation (7Jerusalinsky D. Fin C. Quillfeldt J.A. Ferreira M.B. Schmitz P.K. Da Silva R.C. Walz R. Bazan N.G. Medina J.H. Izquierdo I. Behav. Neural Biol. 1994; 62: 1-3Crossref PubMed Scopus (26) Google Scholar, 8Izquierdo I. Fin C. Schmitz P.K. Da Silva R.C. Jerusalinsky D. Quillfeldt J.A. Ferreira M.B.G. Medina J.H. Bazan N.G. Proc. Natl. Acad. Sci. U. S. A. 1995; 92: 5047-5051Crossref PubMed Scopus (110) Google Scholar, 9Packard M. Teather L. Bazan N.G. Neurobiol. Learn. Mem. 1996; 66: 176-182Crossref PubMed Scopus (60) Google Scholar). PAF is synthetized through several pathways (10Bazan N.G. Nature. 1995; 374: 501-502Crossref PubMed Scopus (69) Google Scholar). The PAF precursor is enriched in arachidonate at the C2 position. The Ca2+-dependent PAF remodeling pathway engages a phospholipase A2, followed by acetylation to give rise to PAF (11Prescott S.M. Zimmerman G.A. McIntyre T.M. J. Biol. Chem. 1990; 265: 17381-17384Abstract Full Text PDF PubMed Google Scholar). Neuronal stimulation, such as at the onset of seizures or from ischemia, promotes the rapid release of arachidonic acid (12Dumuis A. Pin J.P. Oomagari K. Sebben M. Bockaert J. Nature. 1990; 347: 182-184Crossref PubMed Scopus (189) Google Scholar, 13Williams R.J. Murphy N. Glowinski J. Prémont J. J. Neurochem. 1995; 65: 241-249Crossref PubMed Scopus (25) Google Scholar), reflecting synaptic phospholipase A2 activation (14Bazan N.G. Biochim. Biophys. Acta. 1970; 218: 1-10Crossref PubMed Scopus (699) Google Scholar, 15Aveldaño M.I. Bazan N.G. Brain Res. 1975; 100: 99-110Crossref PubMed Scopus (68) Google Scholar). The cytosolic form of phospholipase A2 is important in postischemic neuronal cell death as is shown using knockout cPLA2 mice (16Bonventre J.V. Huang Z. Taheri M.R. O'Leary E. Li E. Moskowitz M.A. Sapirstein A. Nature. 1997; 390: 622-625Crossref PubMed Scopus (763) Google Scholar). Also, a secretory PLA2 may contribute to excitotoxicity (17Kolko M. DeCoster M.A. Rodriguez de Turco E.B. Bazan N.G. J. Biol. Chem. 1996; 271: 32722-32728Abstract Full Text Full Text PDF PubMed Scopus (92) Google Scholar, 18Clapp L.E. Klette K.L. DeCoster M.A. Bernton E. Petras J.M. Dave J.R. Laskosky M.S. Smallridge R.C. Tortella F.C. Brain Res. 1995; 693: 101-111Crossref PubMed Scopus (33) Google Scholar). Again, the signaling events are not clear. In brain ischemia and seizures, there is also PAF accumulation (19Yue T.L. Lysko P.G. Feuerstein G. J. Neurochem. 1990; 54: 1809-1811Crossref PubMed Scopus (79) Google Scholar, 20Nishida K. Markey S.P. Stroke. 1996; 27: 514-518Crossref PubMed Scopus (37) Google Scholar), which in turn, contributes to increased glutamate release (5Clark G.D. Happel L.T. Zorumski C.F. Bazan N.G. Neuron. 1992; 9: 1211-1216Abstract Full Text PDF PubMed Scopus (189) Google Scholar) and COX-2 transcription (21Bazan N.G. Fletcher B.S. Herschman H.R. Mukherjee P.K. Proc. Natl. Acad. Sci. 1994; 91: 5252-5256Crossref PubMed Scopus (135) Google Scholar, 22Marcheselli V.L. Bazan N.G. J. Biol. Chem. 1996; 271: 24794-24799Abstract Full Text Full Text PDF PubMed Scopus (145) Google Scholar), both enhancing brain injury. Therefore, PAF is a neuronal injury mediator, and consequently, PAF antagonists elicit neuroprotection (23Gilboe D.D. Kintner D. Fitzpatrick J.H. Emoto S.E. Esanu A. Braquet P.G. Bazan N.G. J. Neurochem. 1991; 56: 311-319Crossref PubMed Scopus (69) Google Scholar, 24Panetta T. Marcheselli V.L. Braquet P. Spinnewyn B. Bazan N.G. Biochem. Biophys. Res. Commun. 1987; 149: 580-587Crossref PubMed Scopus (136) Google Scholar). Both PAF (25Honda Z. Takano T. Gotoh Y. Nishida E. Ito K. Shimizu T. J. Biol. Chem. 1994; 269: 2307-2315Abstract Full Text PDF PubMed Google Scholar, 26Fouda S.I. Molski T.F. Ashour M.S. Sha'afi R.I. Biochem. J. 1995; 308: 815-822Crossref PubMed Scopus (51) Google Scholar, 27Bonaccorsi L. Luconi M. Maggi M. Muratori M. Forti G. Serio M. Baldi E. Biochim. Biophys. Acta. 1997; 1355: 155-166Crossref PubMed Scopus (23) Google Scholar) and glutamate (28Bading H. Greenberg M.E. Science. 1991; 253: 912-914Crossref PubMed Scopus (430) Google Scholar, 29Fiore R.S. Murphy T.H. Sanghera J.S. Pelech S.L. Baraban J.M. J. Neurochem. 1993; 61: 1626-1633Crossref PubMed Scopus (138) Google Scholar, 30Kurino M. Fukunaga K. Ushio Y. Miyamoto E. J. Neurochem. 1995; 65: 1282-1289Crossref PubMed Scopus (144) Google Scholar) activate MAP kinases. These studies directly implicate PAF as a second messenger in a glutamate-induced signaling pathway. We used primary rat hippocampal neuronal cultures to determine whether the injury/inflammatory messenger PAF is a mediator of NMDA activation of JNK, p38, and ERK MAP kinases. Furthermore, we have explored whether metabotropic receptor activation affects NMDA receptor signaling to stress-sensitive MAP kinases and have examined the consequences of glutamate receptor interplay through PAF signaling on neuroprotection. Culture plates were coated with Matrigel (Collaborative Research). Hippocampi from 1–3-day old rat pups were pooled in oxygenated Liebovitz's (L-15) medium plus 0.05% bovine serum albumin. Hippocampi were then moved to a solution of 0.1% papain in L-15 + bovine serum albumin for 20 min (under oxygen) and then triturated with a Pasteur pipette. Cells were plated at 500,000 cells/ml in minimal essential medium plus 10% fetal calf and horse serum supplemented with insulin, transferrin, and selenium and with glucose and glutamine and then maintained in 37 °C, 5% CO2 incubators (5Clark G.D. Happel L.T. Zorumski C.F. Bazan N.G. Neuron. 1992; 9: 1211-1216Abstract Full Text PDF PubMed Scopus (189) Google Scholar). After 1 day in vitro, cultures were treated with 10−5mAra-C. After 4 days in vitro, Ara-C was removed and cells moved to fresh minimal essential medium lacking serum. All experiments were carried on cultures days in vitro. were in and were not treated with of fetal calf and horse serum were carried on the cultures cells were from the and with to a cell and then in medium and for These cultures were then with medium using for experiments as M.A. J. 1994; PubMed Scopus Google Scholar). cultures were to antagonists in solution and supplemented with 1 to the activation of the NMDA of cells to PAF was carried in medium as in the medium was cells were then with in and at for min at 4 and the used for the and were as protein were with protein and then with of and or for at 4 JNK3 was from The were with and with kinase 20 20 and of were for min at using of of or of protein and 20 at in of kinase as M. A. T. A. M. 1993; PubMed Scopus Google Scholar). The were by 20 of and of to the and on The were with of acid followed by with After using a of by was using a were at in solution and supplemented with 1 Cells were treated with in or solution for Cells were then in minimal essential medium and were to the CO2 minimal essential was removed from the cells were with and of cell and cell were for to release using with the of a and neuroprotection was M.A. Klette K.L. Tortella F.C. Brain Res. 1995; Scopus Google Scholar). After the cells were with and and were using cells were primary rat hippocampal neuronal cultures in the of and in the of 1 NMDA activates ERK JNK p38 A and NMDA promotes the rapid activation of these MAP kinases, at p38 MAP kinase and JNK activation are ERK activation is of NMDA 1 The NMDA receptor antagonist NMDA stimulation of the protein kinases 1 the of PAF as a mediator of NMDA the BN50730 intracellular PAF receptor antagonist V.L. Bazan N.G. J. Biol. Chem. 1996; 271: 24794-24799Abstract Full Text Full Text PDF PubMed Scopus (145) Google Scholar, V.L. M. Braquet P. Bazan N.G. J. Biol. Chem. 1990; 265: Full Text PDF PubMed Google Scholar), was used and was to NMDA stimulation of the protein kinases to to that of 1 The bioactive PAF is a candidate mediator of excitatory amino acid signaling because it is a retrograde messenger of (3Kato K. Clark G.D. Bazan N.G. Zorumski C.F. Nature. 1994; 367: 175-179Crossref PubMed Scopus (225) Google Scholar, 4Wieraszko A. Li G. Kornecki E. Hogan M.V. Ehrlich Y.H. Neuron. 1993; 10: 553-557Abstract Full Text PDF PubMed Scopus (145) Google Scholar) that enhances glutamate release (5Clark G.D. Happel L.T. Zorumski C.F. Bazan N.G. Neuron. 1992; 9: 1211-1216Abstract Full Text PDF PubMed Scopus (189) Google Scholar), is generated by NMDA receptor activation (6Nishida K. Markey S.P. Kustova Y. Mores H.C. Skolnick P. Basile A.S. Sei Y. J. Neurochem. 1996; 66: 433-435Crossref PubMed Scopus (41) Google Scholar), and participates in memory formation I. Fin C. Schmitz P.K. Da Silva R.C. Jerusalinsky D. Quillfeldt J.A. Ferreira M.B.G. Medina J.H. Bazan N.G. Proc. Natl. Acad. Sci. U. S. A. 1995; 92: 5047-5051Crossref PubMed Scopus (110) Google Scholar). PAF is synthetized through several pathways (10Bazan N.G. Nature. 1995; 374: 501-502Crossref PubMed Scopus (69) Google Scholar). The PAF precursor is enriched in arachidonate at the C2 position. The Ca2+-dependent PAF remodeling pathway engages a phospholipase A2, followed by acetylation to give rise to PAF (11Prescott S.M. Zimmerman G.A. McIntyre T.M. J. Biol. Chem. 1990; 265: 17381-17384Abstract Full Text PDF PubMed Google Scholar). Brain stimulation, such as at the onset of seizures or from ischemia, promotes the rapid release of arachidonic reflecting synaptic phospholipase A2 activation (14Bazan N.G. Biochim. Biophys. Acta. 1970; 218: 1-10Crossref PubMed Scopus (699) Google Scholar). of BN50730 on MAP kinase activation that PAF is a messenger in this signaling pathway. Therefore, to whether PAF activates MAP kinases, we hippocampal neurons with of this PAF at 1 and JNK and p38 MAP kinase in hippocampal neurons and JNK is in the of PAF, p38 MAP kinase activation to these ERK, on the is at and at of PAF, a in was We the of PAF receptor antagonist that PAF from V.L. M. Braquet P. Bazan N.G. J. Biol. Chem. 1990; 265: Full Text PDF PubMed Google Scholar), blocks glutamate release (5Clark G.D. Happel L.T. Zorumski C.F. Bazan N.G. Neuron. 1992; 9: 1211-1216Abstract Full Text PDF PubMed Scopus (189) Google Scholar), and (3Kato K. Clark G.D. Bazan N.G. Zorumski C.F. Nature. 1994; 367: 175-179Crossref PubMed Scopus (225) Google Scholar), of and MAP kinase activation not However, the intracellular PAF antagonist BN50730 blocks JNK, p38, and ERK the PAF receptor from directly involved in MAP kinase is not whether PAF receptors are involved to a because is a of MAP kinase activation by The NMDA receptor antagonist and the receptor antagonist were to MAP kinase that PAF of the glutamate receptor and the cultures used in the experiments 10% the of to and MAP kinase activation was that from the not to PAF or NMDA as neurons. JNK and p38 of are not by PAF, ERK is to a in neurons. NMDA receptor PLA2 activation A. Sebben M. L. Pin J.P. Bockaert J. Nature. PubMed Scopus Google Scholar) and PAF (6Nishida K. Markey S.P. Kustova Y. Mores H.C. Skolnick P. Basile A.S. Sei Y. J. Neurochem. 1996; 66: 433-435Crossref PubMed Scopus (41) Google Scholar). Therefore, PAF is a messenger in stress-sensitive MAP kinase the of this to the this of PAF this McIntyre T.M. 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Nature. 1995; 374: PubMed Scopus Google Scholar) and neuroprotection NMDA in primary hippocampal neuronal of hippocampal neurons with recombinant PAF the activation of MAP kinases All of the were using NMDA or PAF as Therefore, the of glutamate were was that activation of stress-sensitive MAP kinases have at a that PAF as a glutamate was to activate MAP kinases through a to the PAF receptor BN50730 MAP kinases from hippocampal are by glutamate are to and The NMDA receptor antagonist blocks glutamate activation of MAP kinases at or Therefore, NMDA activates MAP kinases through a BN50730 of the NMDA receptor and glutamate not BN50730 The of the PAF receptor antagonist BN50730 to activation of stress-sensitive MAP kinases that glutamate and PAF pathways for the activation of these protein kinases, or that by the metabotropic receptor is the NMDA-stimulated signaling pathway that this we the of metabotropic and A that a glutamate metabotropic receptor with NMDA, inhibits activation of ERK, JNK, and a mGluR the and for BN50730 to of the MAP kinases acid also activates the MAP to this pathway The on ERK and JNK was using kinase and of kinase that NMDA the and ERK by and The JNK were increased and for the and these of NMDA, as by kinase and in with the by and We the of as a metabotropic of the NMDA mGluR, we that the by this glutamate receptor on the NMDA this hippocampal neurons were with the metabotropic receptor followed by these the of glutamate is a metabotropic receptor inhibits NMDA activation of stress-sensitive MAP kinases. and or at the of the min with or NMDA or The metabotropic receptor antagonist or of NMDA by was min NMDA was are S.E. from to has on activation of MAP kinases. The receptor antagonist inhibits activation of kinases. are of to In kinase was by of protein cell using as ERK and as JNK by with NMDA + Glutamate is for metabotropic the MAP kinase by glutamate is the of NMDA, and metabotropic receptor we whether MAP kinase by to MAP kinases, we that and of ERK, JNK, and In using the of hippocampal we that MAP kinase activation by NMDA was by to the of and for ERK, JNK, and p38, also that the metabotropic receptor antagonist also activation of the MAP kinases However, is a receptor the in studies may because of at neuronal A. L. J. 1996; PubMed Google Scholar). The of MAP kinase activation the used is the NMDA that the used of the hippocampal neurons to NMDA, glutamate or in this were for the activation of the NMDA receptor, with and in the solution 1 The MAP kinases are of pathways involved in cell and The hippocampal neurons used in the experiments are the protein kinase activation cell signaling through which the bioactive in synaptic in the in the form of are by activation of MAP kinase J. Biol. Chem. 1996; 271: Full Text Full Text PDF PubMed Scopus Google Scholar). The signaling through PAF to stress-sensitive MAP kinase activation may also participate in cell this of neuronal cell injury and with were used hippocampal cultures a of cell in the with DAPI, cultures and cultures treated with BN50730 plus NMDA multiple experiments a of BN50730 cell as by 4 These results were in the cultures used for with of which neuroprotection by BN50730 NMDA 4 was also or was The NMDA receptor antagonist as a was in neuroprotection to glutamate was used as neuroprotection by the PAF receptor antagonist BN50730 was in the of the metabotropic glutamate receptor In with these of glutamate metabotropic receptors neuroprotection in injury E. Proc. Natl. Acad. Sci. U. S. A. 1991; PubMed Scopus Google Scholar). However, studies have the of mGluR Y. M. Brain Res. 1997; PubMed Scopus Google Scholar, A.S. J.P. D.D. J. 1993; PubMed Google Scholar, D.D. J.P. R.A. A.S. 1995; PubMed Scopus Google Scholar). 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ERK may cPLA2 activation through neuroprotection 4 may PAF to In brain ischemia and seizures, there is also PAF accumulation (19Yue T.L. Lysko P.G. Feuerstein G. J. Neurochem. 1990; 54: 1809-1811Crossref PubMed Scopus (79) Google Scholar, 20Nishida K. Markey S.P. Stroke. 1996; 27: 514-518Crossref PubMed Scopus (37) Google Scholar) in turn, PAF accumulation contributes to increased glutamate release (5Clark G.D. Happel L.T. Zorumski C.F. Bazan N.G. Neuron. 1992; 9: 1211-1216Abstract Full Text PDF PubMed Scopus (189) Google Scholar) and COX-2 transcription V.L. Bazan N.G. J. Biol. Chem. 1996; 271: 24794-24799Abstract Full Text Full Text PDF PubMed Scopus (145) Google Scholar), both enhancing brain injury. Therefore, PAF is a neuronal injury mediator, and consequently, PAF antagonists elicit neuroprotection (23Gilboe D.D. Kintner D. Fitzpatrick J.H. Emoto S.E. Esanu A. Braquet P.G. Bazan N.G. J. Neurochem. 1991; 56: 311-319Crossref PubMed Scopus (69) Google Scholar, 24Panetta T. Marcheselli V.L. Braquet P. Spinnewyn B. Bazan N.G. Biochem. Biophys. Res. Commun. 1987; 149: 580-587Crossref PubMed Scopus (136) Google Scholar). Both PAF (25Honda Z. Takano T. Gotoh Y. Nishida E. Ito K. Shimizu T. J. Biol. Chem. 1994; 269: 2307-2315Abstract Full Text PDF PubMed Google Scholar, 26Fouda S.I. Molski T.F. Ashour M.S. Sha'afi R.I. Biochem. J. 1995; 308: 815-822Crossref PubMed Scopus (51) Google Scholar, 27Bonaccorsi L. Luconi M. Maggi M. Muratori M. Forti G. Serio M. Baldi E. Biochim. Biophys. Acta. 1997; 1355: 155-166Crossref PubMed Scopus (23) Google Scholar) and glutamate (28Bading H. Greenberg M.E. Science. 1991; 253: 912-914Crossref PubMed Scopus (430) Google Scholar, 29Fiore R.S. Murphy T.H. Sanghera J.S. Pelech S.L. Baraban J.M. J. Neurochem. 1993; 61: 1626-1633Crossref PubMed Scopus (138) Google Scholar, 30Kurino M. Fukunaga K. Ushio Y. Miyamoto E. J. Neurochem. 1995; 65: 1282-1289Crossref PubMed Scopus (144) Google Scholar) activate MAP kinases. These studies directly implicate PAF as a second messenger in a glutamate-induced signaling pathway. of glutamate metabotropic receptors may signals generated by receptor (NMDA) as a to the of In this signaling which is by PAF, is by E. Proc. Natl. Acad. Sci. U. S. A. 1991; PubMed Scopus Google Scholar) that neuroprotection of neurons in are inhibits MAP kinase activation by NMDA not by a by NMDA and receptors activates on the pathway from the NMDA receptor The is the of metabotropic receptor the mGluR receptor The of cells specific receptor to whether the of signals from the NMDA receptor by mGluR activation at the of the receptor of PAF or of or at the PAF Also, and such as may modulate the events the activation by PAF of stress-sensitive MAP kinases may to activation of to cell the PAF antagonist BN50730 inhibits COX-2 transcription in cells (21Bazan N.G. Fletcher B.S. Herschman H.R. Mukherjee P.K. Proc. Natl. Acad. Sci. 1994; 91: 5252-5256Crossref PubMed Scopus (135) Google Scholar) as as in vivo hippocampal V.L. Bazan N.G. J. Biol. Chem. 1996; 271: 24794-24799Abstract Full Text Full Text PDF PubMed Scopus (145) Google Scholar). In we have a pathway from NMDA through PAF that activates stress-sensitive kinases and leads to hippocampal neuronal cell death. pathway contributes to the of signals that We that by the metabotropic glutamate receptor, this signaling pathway is We that neuronal cell death a that of results that mGluR and NMDA receptor interplay is important in neuronal death of mGluR that NMDA signaling through PAF may to excitotoxicity and as are to the PAF receptor or to PAF as it