NMDA receptor signaling: death or survival?

Abstract

Glutamate-induced neuronal damage is mainly caused by overactivation of N-methyl-D-aspartate (NMDA) receptors. Conversely, normal physiological brain function and neuronal survival require adequate activation of NMDA receptors. Studies have revealed that NMDA receptor-induced neuronal death or survival is mediated through distinct subset of NMDA receptors triggering different intracellular signaling pathways. Here we discuss recent advances in the characterization of NMDA receptors in neuronal protection, emphasizing subunit-specific role, which contributes to temporal-spatial distribution, subcellular localization and diverse channel properties of NMDA receptors.

Keywords

NMDA receptors / glutamate / excitotoxicity / ischemia / neuroprotection

References

[1] AartsM, LiuY, LiuL, BesshohS, ArundineM, GurdJ W, WangY T, SalterM W, TymianskiM (2002). Treatment of ischemic brain damage by perturbing NMDA receptor- PSD-95 protein interactions.Science, 298(5594): 846–850

[2] Al-MubarakB, SorianoF X, HardinghamG E (2009). Synaptic NMDAR activity suppresses FOXO1 expression via a cis-acting FOXO binding site: FOXO1 is a FOXO target gene.Channels (Austin), 3(4): 233–238

[3] AkazawaC, ShigemotoR, BesshoY, NakanishiS, MizunoN (1994). Differential expression of five N-methyl-D-aspartate receptor subunit mRNAs in the cerebellum of developing and adult rats.J Comp Neurol, 347(1): 150–160

[4] BrunetA, BonniA, ZigmondM J, LinM Z, JuoP, HuL S, AndersonM J, ArdenK C, BlenisJ, GreenbergM E (1999). Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor.Cell, 96(6): 857–868

[5] CavaraN A, HollmannM (2008). Shuffling the deck anew: how NR3 tweaks NMDA receptor function.Mol Neurobiol, 38(1): 16–26

[6] CavaraN A, OrthA, HickingG, SeebohmG, HollmannM (2010). Residues at the tip of the pore loop of NR3B-containing NMDA receptors determine Ca²⁺ permeability and Mg²⁺ block.BMC Neurosci, 11(1): 133

[7] ChandlerL J, SuttonG, DorairajN R, NorwoodD (2001). N-methyl D-aspartate receptor-mediated bidirectional control of extracellular signal-regulated kinase activity in cortical neuronal cultures.J Biol Chem, 276(4): 2627–2636

[8] ChattertonJ E, AwobuluyiM, PremkumarL S, TakahashiH, TalantovaM, ShinY, CuiJ, TuS, SevarinoK A, NakanishiN, TongG, LiptonS A, ZhangD (2002). Excitatory glycine receptors containing the NR3 family of NMDA receptor subunits.Nature, 415(6873): 793–798

[9] ChenB S, RocheK W (2007). Regulation of NMDA receptors by phosphorylation.Neuropharmacology, 53(3): 362–368

[10] ChenB S, RocheK W (2009). Growth factor-dependent trafficking of cerebellar NMDA receptors via protein kinase B/Akt phosphorylation of NR2C.Neuron, 62(4): 471–478

[11] ChoiD W (1987). Ionic dependence of glutamate neurotoxicity.J Neurosci, 7(2): 369–379

[12] ChoiD W, Maulucci-GeddeM, KriegsteinA R (1987). Glutamate neurotoxicity in cortical cell culture.J Neurosci, 7(2): 357–368

[13] ChoiD W, KohJ Y, PetersS (1988). Pharmacology of glutamate neurotoxicity in cortical cell culture: attenuation by NMDA antagonists.J Neurosci, 8(1): 185–196

[14] CiabarraA M, SullivanJ M, GahnL G, PechtG, HeinemannS, SevarinoK A (1995). Cloning and characterization of chi-1: a developmentally regulated member of a novel class of the ionotropic glutamate receptor family.J Neurosci, 15(10): 6498–6508

[15] CianiE, RizziS, PaulsenR E, ContestabileA (1997). Chronic pre-explant blockade of the NMDA receptor affects survival of cerebellar granule cells explanted in vitro.Brain Res Dev Brain Res, 99(1): 112–117

[16] ClementsJ D, LesterR A, TongG, JahrC E, WestbrookG L (1992). The time course of glutamate in the synaptic cleft.Science, 258(5087): 1498–1501

[17] CollingridgeG L, IsaacJ T R, WangY T (2004). Receptor trafficking and synaptic plasticity.Nat Rev Neurosci, 5(12): 952–962

[18] CuiH, HayashiA, SunH S, BelmaresM P, CobeyC, PhanT, SchweizerJ, SalterM W, WangY T, TaskerR A, GarmanD, RabinowitzJ, LuP S, TymianskiM (2007). PDZ protein interactions underlying NMDA receptor-mediated excitotoxicity and neuroprotection by PSD-95 inhibitors.J Neurosci, 27(37): 9901–9915

[19] Cull-CandyS, BrickleyS, FarrantM (2001). NMDA receptor subunits: diversity, development and disease.Curr Opin Neurobiol, 11(3): 327–335

[20] Cull-CandyS G, LeszkiewiczD N (2004). Role of distinct NMDA receptor subtypes at central synapses.Sci STKE, 2004(255): re16

[40] DasS, SasakiY F, RotheT, PremkumarL S, TakasuM, CrandallJ E, DikkesP, ConnerD A, RayuduP V, CheungW, ChenH S, LiptonS A, NakanishiN (1998). Increased NMDA current and spine density in mice lacking the NMDA receptor subunit NR3A.Nature, 393(6683): 377–381

[21] DickO, BadingH (2010). Synaptic activity and nuclear calcium signaling protect hippocampal neurons from death signal-associated nuclear translocation of FoxO3a induced by extrasynaptic N-methyl-D-aspartate receptors.J Biol Chem, 285(25): 19354–19361

[22] DingledineR, BorgesK, BowieD, TraynelisS F (1999). The glutamate receptor ion channels.Pharmacol Rev, 51(1): 7–61

[23] DravidS M, PrakashA, TraynelisS F (2008). Activation of recombinant NR1/NR2C NMDA receptors.J Physiol, 586(18): 4425–4439

[24] EbralidzeA K, RossiD J, TonegawaS, SlaterN T (1996). Modification of NMDA receptor channels and synaptic transmission by targeted disruption of the NR2C gene.J Neurosci, 16(16): 5014–5025

[25] von EngelhardtJ, CosereaI, PawlakV, FuchsE C, KöhrG, SeeburgP H, MonyerH, (2007). Excitotoxicity in vitro by NR2A- and NR2B-containing NMDA receptors.Neuropharmacology, 53(1): 10–17

[26] FarrantM, FeldmeyerD, TakahashiT, Cull-CandyS G (1994). NMDA-receptor channel diversity in the developing cerebellum.Nature, 368(6469): 335–339

[27] GrocL, HeineM, CousinsS L, StephensonF A, LounisB, CognetL, ChoquetD (2006). NMDA receptor surface mobility depends on NR2A-2B subunits.Proc Natl Acad Sci USA, 103(49): 18769–18774

[28] HardinghamG E, BadingH (2010). Synaptic versus extrasynaptic NMDA receptor signalling: implications for neurodegenerative disorders.Nat Rev Neurosci, 11(10): 682–696

[29] HardinghamG E, FukunagaY, BadingH (2002). Extrasynaptic NMDARs oppose synaptic NMDARs by triggering CREB shut-off and cell death pathways.Nat Neurosci, 5(5): 405–414

[30] IkonomidouC, BoschF, MiksaM, BittigauP, VöcklerJ, DikranianK, TenkovaT I, StefovskaV, TurskiL, OlneyJ W (1999). Blockade of NMDA receptors and apoptotic neurodegeneration in the developing brain.Science, 283(5398): 70–74

[31] IvanovA, PellegrinoC, RamaS, DumalskaI, SalyhaY, Ben-AriY, MedinaI (2006). Opposing role of synaptic and extrasynaptic NMDA receptors in regulation of the extracellular signal-regulated kinases (ERK) activity in cultured rat hippocampal neurons.J Physiol, 572(Pt 3): 789–798

[32] KadotaniH, NamuraS, KatsuuraG, TerashimaT, KikuchiH (1998). Attenuation of focal cerebral infarct in mice lacking NMDA receptor subunit NR2C.Neuroreport, 9(3): 471–475

[33] KaravanovaI, VasudevanK, ChengJ, BuonannoA (2007). Novel regional and developmental NMDA receptor expression patterns uncovered in NR2C subunit-beta-galactosidase knock-in mice.Mol Cell Neurosci, 34(3): 468–480

[34] KáradóttirR, CavelierP, BergersenL H, AttwellD (2005). NMDA receptors are expressed in oligodendrocytes and activated in ischaemia.Nature, 438(7071): 1162–1166

[35] KimM J, DunahA W, WangY T, ShengM (2005). Differential roles of NR2A- and NR2B-containing NMDA receptors in Ras-ERK signaling and AMPA receptor trafficking.Neuron, 46(5): 745–760

[36] KutsuwadaT, SakimuraK, ManabeT, TakayamaC, KatakuraN, KushiyaE, NatsumeR, WatanabeM, InoueY, YagiT, AizawaS, ArakawaM, TakahashiT, NakamuraY, MoriH, MishinaM (1996). Impairment of suckling response, trigeminal neuronal pattern formation, and hippocampal LTD in NMDA receptor epsilon 2 subunit mutant mice.Neuron, 16(2): 333–344

[37] LarsenR S, CorlewR J, HensonM A, RobertsA C, MishinaM, WatanabeM, LiptonS A, NakanishiN, Pérez-OtañoI, WeinbergR J, PhilpotB D (2011). NR3A-containing NMDARs promote neurotransmitter release and spike timing-dependent plasticity.Nat Neurosci, 14(3): 338–344

[38] LeeF J S, XueS, PeiL, VukusicB, ChéryN, WangY, WangY T, NiznikH B, YuX M, LiuF (2002). Dual regulation of NMDA receptor functions by direct protein-protein interactions with the dopamine D1 receptor.Cell, 111(2): 219–230

[39] LehtinenM K, YuanZ, BoagP R, YangY, VillénJ, BeckerE B E, DiBaccoS, de la IglesiaN, GygiS, BlackwellT K, BonniA (2006). A conserved MST-FOXO signaling pathway mediates oxidative-stress responses and extends life span.Cell, 125(5): 987–1001

[41] LiuY, WongT P, AartsM, RooyakkersA, LiuL, LaiT W, WuD C, LuJ, TymianskiM, CraigA M, WangY T (2007). NMDA receptor subunits have differential roles in mediating excitotoxic neuronal death both in vitro and in vivo.J Neurosci, 27(11): 2846–2857

[42] LowC M, WeeK S L (2010). New insights into the not-so-new NR3 subunits of N-methyl-D-aspartate receptor: localization, structure, and function.Mol Pharmacol, 78(1): 1–11

[43] LucasD R, NewhouseJ P (1957). The toxic effect of sodium L-glutamate on the inner layers of the retina.AMA Arch Ophthalmol, 58(2): 193–201

[44] MartelM A, WyllieD J, HardinghamG E (2009). In developing hippocampal neurons, NR2B-containing N-methyl-D-aspartate receptors (NMDARs) can mediate signaling to neuronal survival and synaptic potentiation, as well as neuronal death.Neuroscience, 158(1): 334–343

[45] MayrB, MontminyM (2001). Transcriptional regulation by the phosphorylation-dependent factor CREB.Nat Rev Mol Cell Biol, 2(8): 599–609

[46] MicuI, JiangQ, CoderreE, RidsdaleA, ZhangL, WoulfeJ, YinX, TrappB D, McRoryJ E, RehakR, ZamponiG W, WangW, StysP K (2006). NMDA receptors mediate calcium accumulation in myelin during chemical ischaemia.Nature, 439(7079): 988–992

[47] MonyerH, BurnashevN, LaurieD J, SakmannB, SeeburgP H (1994). Developmental and regional expression in the rat brain and functional properties of four NMDA receptors.Neuron, 12(3): 529–540

[48] NakanishiN, TuS, ShinY, CuiJ, KurokawaT, ZhangD, ChenH S V, TongG, LiptonS A (2009). Neuroprotection by the NR3A subunit of the NMDA receptor.J Neurosci, 29(16): 5260–5265

[49] NakazawaK, McHughT J, WilsonM A, TonegawaS (2004). NMDA receptors, place cells and hippocampal spatial memory.Nat Rev Neurosci, 5(5): 361–372

[50] NeytonJ, PaolettiP (2006). Relating NMDA receptor function to receptor subunit composition: limitations of the pharmacological approach.J Neurosci, 26(5): 1331–1333

[51] NiH, JiangY W, BoT, WangJ M, WuX R (2005). c-Fos, N-methyl-d-aspartate receptor 2C, GABA-A-alpha1 immonoreactivity, seizure latency and neuronal injury following single or recurrent neonatal seizures in hippocampus of Wistar rat.Neurosci Lett, 380(1–2): 149–154

[52] NiethammerM, KimE, ShengM (1996). Interaction between the C terminus of NMDA receptor subunits and multiple members of the PSD-95 family of membrane-associated guanylate kinases.J Neurosci, 16(7): 2157–2163

[53] NishiM, HindsH, LuH P, KawataM, HayashiY (2001). Motoneuron-specific expression of NR3B, a novel NMDA-type glutamate receptor subunit that works in a dominant-negative manner.J Neurosci, 21(23): RC185

[54] OlneyJ W, SharpeL G (1969). Brain lesions in an infant rhesus monkey treated with monsodium glutamate.Science, 166(3903): 386–388

[55] PapadiaS, SorianoF X, LéveilléF, MartelM A, DakinK A, HansenH H, KaindlA, SifringerM, FowlerJ, StefovskaV, McKenzieG, CraigonM, CorriveauR, GhazalP, HorsburghK, YanknerB A, WyllieD J A, IkonomidouC, HardinghamG E (2008). Synaptic NMDA receptor activity boosts intrinsic antioxidant defenses.Nat Neurosci, 11(4): 476–487

[56] Pérez-OtañoI, LujánR, TavalinS J, PlomannM, ModreggerJ, LiuX B, JonesE G, HeinemannS F, LoD C, EhlersM D (2006). Endocytosis and synaptic removal of NR3A-containing NMDA receptors by PACSIN1/syndapin1.Nat Neurosci, 9(5): 611–621

[57] Piña-CrespoJ C, TalantovaM, MicuI, StatesB, ChenH S V, TuS, NakanishiN, TongG, ZhangD, HeinemannS F, ZamponiG W, StysP K, LiptonS A (2010). Excitatory glycine responses of CNS myelin mediated by NR1/NR3 “NMDA” receptor subunits.J Neurosci, 30(34): 11501–11505

[58] SakimuraK, KutsuwadaT, ItoI, ManabeT, TakayamaC, KushiyaE, YagiT, AizawaS, InoueY, SugiyamaH, MishinaM (1995). Reduced hippocampal LTP and spatial learning in mice lacking NMDA receptor epsilon 1 subunit.Nature, 373(6510): 151–155

[59] SalterM G, FernR (2005). NMDA receptors are expressed in developing oligodendrocyte processes and mediate injury.Nature, 438(7071): 1167–1171

[60] SasakiT, TakemoriH, YagitaY, TerasakiY, UebiT, HorikeN, TakagiH, SusumuT, TeraokaH, KusanoK I, HatanoO, OyamaN, SugiyamaY, SakodaS, KitagawaK (2011). SIK2 is a key regulator for neuronal survival after ischemia via TORC1-CREB.Neuron, 69(1): 106–119

[61] SasakiY F, RotheT, PremkumarL S, DasS, CuiJ, TalantovaM V, WongH K, GongX, ChanS F, ZhangD, NakanishiN, SucherN J, LiptonS A (2002). Characterization and comparison of the NR3A subunit of the NMDA receptor in recombinant systems and primary cortical neurons.J Neurophysiol, 87(4): 2052–2063

[62] SmallD L, PoulterM O, BuchanA M, MorleyP (1997). Alteration in NMDA receptor subunit mRNA expression in vulnerable and resistant regions of in vitro ischemic rat hippocampal slices.Neurosci Lett, 232(2): 87–90

[63] SattlerR, XiongZ, LuW Y, HafnerM, MacDonaldJ F, TymianskiM (1999). Specific coupling of NMDA receptor activation to nitric oxide neurotoxicity by PSD-95 protein.Science, 284(5421): 1845–1848

[64] SprengelR, SuchanekB, AmicoC, BrusaR, BurnashevN, RozovA, HvalbyO, JensenV, PaulsenO, AndersenP, KimJ J, ThompsonR F, SunW, WebsterL C, GrantS G, EilersJ, KonnerthA, LiJ, McNamaraJ O, SeeburgP H (1998). Importance of the intracellular domain of NR2 subunits for NMDA receptor function in vivo.Cell, 92(2): 279–289

[65] SteigerwaldF, SchulzT W, SchenkerL T, KennedyM B, SeeburgP H, KöhrG (2000). C-Terminal truncation of NR2A subunits impairs synaptic but not extrasynaptic localization of NMDA receptors.J Neurosci, 20(12): 4573–4581

[66] SternP, BéhéP, SchoepferR, ColquhounD (1992). Single-channel conductances of NMDA receptors expressed from cloned cDNAs: comparison with native receptors.Proc Biol Sci, 250(1329): 271–277

[67] SucherN J, AkbarianS, ChiC L, LeclercC L, AwobuluyiM, DeitcherD L, WuM K, YuanJ P, JonesE G, LiptonS A (1995). Developmental and regional expression pattern of a novel NMDA receptor-like subunit (NMDAR-L) in the rodent brain.J Neurosci, 15(10): 6509–6520

[68] TraynelisS F, WollmuthL P, McBainC J, MennitiF S, VanceK M, OgdenK K, HansenK B, YuanH, MyersS J, DingledineR (2010). Glutamate receptor ion channels: structure, regulation, and function.Pharmacol Rev, 62(3): 405–496

[69] ThomasC G, MillerA J, WestbrookG L (2006). Synaptic and extrasynaptic NMDA receptor NR2 subunits in cultured hippocampal neurons.J Neurophysiol, 95(3): 1727–1734

[70] TongG, TakahashiH, TuS, ShinY, TalantovaM, ZagoW, XiaP, NieZ, GoetzT, ZhangD, LiptonS A, NakanishiN (2007). Modulation of NMDA receptor properties and synaptic transmission by the NR3A subunit in mouse hippocampal and cerebrocortical neurons.J Neurophysiol, 99(1): 122–132

[71] TovarK R, WestbrookG L (1999). The incorporation of NMDA receptors with a distinct subunit composition at nascent hippocampal synapses in vitro.J Neurosci, 19(10): 4180–4188

[72] TuW, XuX, PengL, ZhongX, ZhangW, SoundarapandianM M, BalelC, WangM, JiaN, ZhangW, LewF, ChanS L, ChenY, LuY (2010). DAPK1 interaction with NMDA receptor NR2B subunits mediates brain damage in stroke.Cell, 140(2): 222–234

[73] UlbrichM H, IsacoffE Y (2008). Rules of engagement for NMDA receptor subunits.Proc Natl Acad Sci USA, 105(37): 14163–14168

[74] WenzelA, FritschyJ M, MohlerH, BenkeD (1997). NMDA receptor heterogeneity during postnatal development of the rat brain: differential expression of the NR2A, NR2B, and NR2C subunit proteins.J Neurochem, 68(2): 469–478

[75] WeeK S, ZhangY, KhannaS, LowC M (2008). Immunolocalization of NMDA receptor subunit NR3B in selected structures in the rat forebrain, cerebellum, and lumbar spinal cord.J Comp Neurol, 509(1): 118–135

[76] YaoY, HarrisonC B, FreddolinoP L, SchultenK, MayerM L (2008). Molecular mechanism of ligand recognition by NR3 subtype glutamate receptors.EMBO J, 27(15): 2158–2170

[77] ZhouL, LiF, XuH B, LuoC X, WuH Y, ZhuM M, LuW, JiX, ZhouQ G, ZhuD Y (2010). Treatment of cerebral ischemia by disrupting ischemia-induced interaction of nNOS with PSD-95.Nat Med, 16(12): 1439–1443

[78] ZukinR S, BennettM V (1995). Alternatively spliced isoforms of the NMDARI receptor subunit.Trends Neurosci, 18(7): 306–313

Acknowledgments

This work was supported by a NINDS Career Transition Award (to B.-S. C.). We apologize to authors whose work could not be cited due to space constraints.

RIGHTS & PERMISSIONS

2014 Higher Education Press and Springer-Verlag Berlin Heidelberg