Abstract
NMDA receptors play an important physiological role in regulating synaptic plasticity, learning and memory. GluN2A subunits are the most abundant functional subunits of NMDA receptors expressed in mature brain, and their dysfunction is related to various neurological diseases. According to subunit composition, GluN2A-containing NMDA receptors can be divided into two types: diheteromeric and triheteromeric receptors. In this review, the expression, functional and pharmacological properties of different kinds of GluN2A-containing NMDA receptors as well as selective GluN2A regulators were described to further understand this type of NMDA receptors.
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References
Addis L, Virdee JK, Vidler LR, Collier DA, Pal DK, Ursu D (2017) Epilepsy-associated GRIN2A mutations reduce NMDA receptor trafficking and agonist potency—molecular profiling and functional rescue. Sci Rep 7(1):66. https://doi.org/10.1038/s41598-017-00115-w
Al-Hallaq RA, Jarabek BR, Fu Z, Vicini S, Wolfe BB, Yasuda RP (2002) Association of NR3A with the N-methyl-D-aspartate receptor NR1 and NR2 subunits. Mol Pharmacol 62(5):1119–1127. https://doi.org/10.1124/mol.62.5.1119
Al-Hallaq RA, Conrads TP, Veenstra TD, Wenthold RJ (2007) NMDA di-heteromeric receptor populations and associated proteins in rat hippocampus. J Neurosci 27(31):8334–8343. https://doi.org/10.1523/JNEUROSCI.2155-07.2007
Alsabban AH, Morikawa M, Tanaka Y, Takei Y, Hirokawa N (2020) Kinesin Kif3b mutation reduces NMDAR subunit NR2A trafficking and causes schizophrenia-like phenotypes in mice. EMBO J 39(1):e101090. https://doi.org/10.15252/embj.2018101090
Alshammari TK (2020) The ketamine antidepressant story: new insights. Molecules. https://doi.org/10.3390/molecules25235777
Amador A, Bostick CD, Olson H, Peters J, Camp CR, Krizay D, Chen W, Han W, Tang W, Kanber A, Kim S, Teoh J, Sah M, Petri S, Paek H, Kim A, Lutz CM, Yang M, Myers SJ, Bhattacharya S, Yuan H, Goldstein DB, Poduri A, Boland MJ, Traynelis SF, Frankel WN (2020) Modelling and treating GRIN2A developmental and epileptic encephalopathy in mice. Brain 143(7):2039–2057. https://doi.org/10.1093/brain/awaa147
Amantea D, Bagetta G (2017) Excitatory and inhibitory amino acid neurotransmitters in stroke: from neurotoxicity to ischemic tolerance. Curr Opin Pharmacol 35:111–119. https://doi.org/10.1016/j.coph.2017.07.014
Amico-Ruvio SA, Paganelli MA, Myers JM, Popescu GK (2012) Ifenprodil effects on GluN2B-containing glutamate receptors. Mol Pharmacol 82(6):1074–1081. https://doi.org/10.1124/mol.112.078998
Amidfar M, Woelfer M, Reus GZ, Quevedo J, Walter M, Kim YK (2019) The role of NMDA receptor in neurobiology and treatment of major depressive disorder: Evidence from translational research. Prog Neuropsychopharmacol Biol Psychiatry 94:109668. https://doi.org/10.1016/j.pnpbp.2019.109668
Anastasio NC, Xia Y, O’Connor ZR, Johnson KM (2009) Differential role of N-methyl-D-aspartate receptor subunits 2A and 2B in mediating phencyclidine-induced perinatal neuronal apoptosis and behavioral deficits. Neuroscience 163(4):1181–1191. https://doi.org/10.1016/j.neuroscience.2009.07.058
Auberson YP, Allgeier H, Bischoff S, Lingenhoehl K, Moretti R, Schmutz M (2002) 5-Phosphonomethylquinoxalinediones as competitive NMDA receptor antagonists with a preference for the human 1A/2A, rather than 1A/2B receptor composition. Bioorg Med Chem Lett 12(7):1099–1102. https://doi.org/10.1016/s0960-894x(02)00074-4
Babaei P (2021) NMDA and AMPA receptors dysregulation in Alzheimer’s disease. Eur J Pharmacol 908:174310. https://doi.org/10.1016/j.ejphar.2021.174310
Bajaj G, Hau AM, Hsu P, Gafken PR, Schimerlik MI, Ishmael JE (2014) Identification of an atypical calcium-dependent calmodulin binding site on the C-terminal domain of GluN2A. Biochem Biophys Res Commun 444(4):588–594. https://doi.org/10.1016/j.bbrc.2014.01.111
Berberich S, Punnakkal P, Jensen V, Pawlak V, Seeburg PH, Hvalby O, Kohr G (2005) Lack of NMDA receptor subtype selectivity for hippocampal long-term potentiation. J Neurosci 25(29):6907–6910. https://doi.org/10.1523/JNEUROSCI.1905-05.2005
Bettini E, Sava A, Griffante C, Carignani C, Buson A, Capelli AM, Negri M, Andreetta F, Senar-Sancho SA, Guiral L, Cardullo F (2010) Identification and characterization of novel NMDA receptor antagonists selective for NR2A- over NR2B-containing receptors. J Pharmacol Exp Ther 335(3):636–644. https://doi.org/10.1124/jpet.110.172544
Bhattacharya S, Traynelis SF (2018) Unique biology and single-channel properties of GluN2A- and GluN2C-containing triheteromeric N-methyl-D-aspartate receptors. J Exp Neurosci 12:1179069518810423. https://doi.org/10.1177/1179069518810423
Bhattacharya S, Khatri A, Swanger SA, DiRaddo JO, Yi F, Hansen KB, Yuan H, Traynelis SF (2018) Triheteromeric GluN1/GluN2A/GluN2C NMDARs with unique single-channel properties are the dominant receptor population in cerebellar granule cells. Neuron 99(2):315-328 e315. https://doi.org/10.1016/j.neuron.2018.06.010
Boyce-Rustay JM, Holmes A (2006) Genetic inactivation of the NMDA receptor NR2A subunit has anxiolytic- and antidepressant-like effects in mice. Neuropsychopharmacology 31(11):2405–2414. https://doi.org/10.1038/sj.npp.1301039
Buller AL, Larson HC, Schneider BE, Beaton JA, Morrisett RA, Monaghan DT (1994) The molecular basis of NMDA receptor subtypes: native receptor diversity is predicted by subunit composition. J Neurosci 14(9):5471–5484
Burket JA, Deutsch SI (2019) Metabotropic functions of the NMDA receptor and an evolving rationale for exploring NR2A-selective positive allosteric modulators for the treatment of autism spectrum disorder. Prog Neuropsychopharmacol Biol Psychiatry 90:142–160. https://doi.org/10.1016/j.pnpbp.2018.11.017
Cathala L, Misra C, Cull-Candy S (2000) Developmental profile of the changing properties of NMDA receptors at cerebellar mossy fiber-granule cell synapses. J Neurosci 20(16):5899–5905
Chan K, Nestor J, Huerta TS, Certain N, Moody G, Kowal C, Huerta PT, Volpe BT, Diamond B, Wollmuth LP (2020) Lupus autoantibodies act as positive allosteric modulators at GluN2A-containing NMDA receptors and impair spatial memory. Nat Commun 11(1):1403. https://doi.org/10.1038/s41467-020-15224-w
Chatterton JE, Awobuluyi M, Premkumar LS, Takahashi H, Talantova M, Shin Y, Cui J, Tu S, Sevarino KA, Nakanishi N, Tong G, Lipton SA, Zhang D (2002) Excitatory glycine receptors containing the NR3 family of NMDA receptor subunits. Nature 415(6873):793–798. https://doi.org/10.1038/nature715
Chazot PL, Stephenson FA (1997) Molecular dissection of native mammalian forebrain NMDA receptors containing the NR1 C2 exon: direct demonstration of NMDA receptors comprising NR1, NR2A, and NR2B subunits within the same complex. J Neurochem 69(5):2138–2144. https://doi.org/10.1046/j.1471-4159.1997.69052138.x
Chazot PL, Coleman SK, Cik M, Stephenson FA (1994) Molecular characterization of N-methyl-D-aspartate receptors expressed in mammalian cells yields evidence for the coexistence of three subunit types within a discrete receptor molecule. J Biol Chem 269(39):24403–24409
Chen N, Luo T, Raymond LA (1999) Subtype-dependence of NMDA receptor channel open probability. J Neurosci 19(16):6844–6854
Chen W, Tankovic A, Burger PB, Kusumoto H, Traynelis SF, Yuan H (2017) Functional evaluation of a De Novo GRIN2A mutation identified in a patient with profound global developmental delay and refractory epilepsy. Mol Pharmacol 91(4):317–330. https://doi.org/10.1124/mol.116.106781
Chen X, Keramidas A, Harvey RJ, Lynch JW (2020) Effects of GluN2A and GluN2B gain-of-function epilepsy mutations on synaptic currents mediated by diheteromeric and triheteromeric NMDA receptors. Neurobiol Dis 140:104850. https://doi.org/10.1016/j.nbd.2020.104850
Cheriyan J, Balsara RD, Hansen KB, Castellino FJ (2016) Pharmacology of triheteromeric N-methyl-D-aspartate receptors. Neurosci Lett 617:240–246. https://doi.org/10.1016/j.neulet.2016.02.032
Chopra DA, Monaghan DT, Dravid SM (2015) Bidirectional effect of pregnenolone sulfate on GluN1/GluN2A N-methyl-D-aspartate receptor gating depending on extracellular calcium and intracellular milieu. Mol Pharmacol 88(4):650–659. https://doi.org/10.1124/mol.115.100396
Ciabarra AM, Sullivan JM, Gahn LG, Pecht G, Heinemann S, Sevarino KA (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
Costa BM, Irvine MW, Fang G, Eaves RJ, Mayo-Martin MB, Skifter DA, Jane DE, Monaghan DT (2010) A novel family of negative and positive allosteric modulators of NMDA receptors. J Pharmacol Exp Ther 335(3):614–621. https://doi.org/10.1124/jpet.110.174144
Das S, Sasaki YF, Rothe T, Premkumar LS, Takasu M, Crandall JE, Dikkes P, Conner DA, Rayudu PV, Cheung W, Chen HS, Lipton SA, Nakanishi N (1998) Increased NMDA current and spine density in mice lacking the NMDA receptor subunit NR3A. Nature 393(6683):377–381. https://doi.org/10.1038/30748
Ding Y, Wang L, Huo Y, Sun Y, Wang L, Gao Z, Sun Y (2020) Roles of GluN2C in cerebral ischemia: GluN2C expressed in different cell types plays different role in ischemic damage. J Neurosci Res 98(6):1188–1197. https://doi.org/10.1002/jnr.24574
Dingledine R, Borges K, Bowie D, Traynelis SF (1999) The glutamate receptor ion channels. Pharmacol Rev 51(1):7–61
Dore K, Stein IS, Brock JA, Castillo PE, Zito K, Sjostrom PJ (2017) Unconventional NMDA Receptor Signaling. J Neurosci 37(45):10800–10807. https://doi.org/10.1523/JNEUROSCI.1825-17.2017
Du Z, Song Y, Chen X, Zhang W, Zhang G, Li H, Chang L, Wu Y (2021) Knockdown of astrocytic Grin2a aggravates beta-amyloid-induced memory and cognitive deficits through regulating nerve growth factor. Aging Cell 20(8):e13437. https://doi.org/10.1111/acel.13437
Ebralidze AK, Rossi DJ, Tonegawa S, Slater NT (1996) Modification of NMDA receptor channels and synaptic transmission by targeted disruption of the NR2C gene. J Neurosci 16(16):5014–5025
Edman S, McKay S, Macdonald LJ, Samadi M, Livesey MR, Hardingham GE, Wyllie DJ (2012) TCN 201 selectively blocks GluN2A-containing NMDARs in a GluN1 co-agonist dependent but non-competitive manner. Neuropharmacology 63(3):441–449. https://doi.org/10.1016/j.neuropharm.2012.04.027
Endele S, Rosenberger G, Geider K, Popp B, Tamer C, Stefanova I, Milh M, Kortum F, Fritsch A, Pientka FK, Hellenbroich Y, Kalscheuer VM, Kohlhase J, Moog U, Rappold G, Rauch A, Ropers HH, von Spiczak S, Tonnies H, Villeneuve N, Villard L, Zabel B, Zenker M, Laube B, Reis A, Wieczorek D, Van Maldergem L, Kutsche K (2010) Mutations in GRIN2A and GRIN2B encoding regulatory subunits of NMDA receptors cause variable neurodevelopmental phenotypes. Nat Genet 42(11):1021–1026. https://doi.org/10.1038/ng.677
Farrant M, Feldmeyer D, Takahashi T, Cull-Candy SG (1994) NMDA-receptor channel diversity in the developing cerebellum. Nature 368(6469):335–339. https://doi.org/10.1038/368335a0
Feng B, Tse HW, Skifter DA, Morley R, Jane DE, Monaghan DT (2004) Structure-activity analysis of a novel NR2C/NR2D-preferring NMDA receptor antagonist: 1-(phenanthrene-2-carbonyl) piperazine-2,3-dicarboxylic acid. Br J Pharmacol 141(3):508–516. https://doi.org/10.1038/sj.bjp.0705644
Franchini L, Carrano N, Di Luca M, Gardoni F (2020) Synaptic GluN2A-containing NMDA receptors: from physiology to pathological synaptic plasticity. Int J Mol Sci. https://doi.org/10.3390/ijms21041538
Frizelle PA, Chen PE, Wyllie DJ (2006) Equilibrium constants for (R)-[(S)-1-(4-bromo-phenyl)-ethylamino]-(2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-5 -yl)-methyl]-phosphonic acid (NVP-AAM077) acting at recombinant NR1/NR2A and NR1/NR2B N-methyl-D-aspartate receptors: Implications for studies of synaptic transmission. Mol Pharmacol 70(3):1022–1032. https://doi.org/10.1124/mol.106.024042
Gao WJ, Yang SS, Mack NR, Chamberlin LA (2021) Aberrant maturation and connectivity of prefrontal cortex in schizophrenia-contribution of NMDA receptor development and hypofunction. Mol Psychiatry. https://doi.org/10.1038/s41380-021-01196-w
Gardoni F, Sgobio C, Pendolino V, Calabresi P, Di Luca M, Picconi B (2012) Targeting NR2A-containing NMDA receptors reduces L-DOPA-induced dyskinesias. Neurobiol Aging 33(9):2138–2144. https://doi.org/10.1016/j.neurobiolaging.2011.06.019
Ge Y, Chen W, Axerio-Cilies P, Wang YT (2020) NMDARs in cell survival and death: implications in stroke pathogenesis and treatment. Trends Mol Med 26(6):533–551. https://doi.org/10.1016/j.molmed.2020.03.001
Geoffroy C, Paoletti P, Mony L (2021) Positive allosteric modulation of NMDA receptors: mechanisms, physiological impact and therapeutic potential. J Physiol. https://doi.org/10.1113/JP280875
Gordillo-Salas M, Pilar-Cuellar F, Auberson YP, Adell A (2018) Signaling pathways responsible for the rapid antidepressant-like effects of a GluN2A-preferring NMDA receptor antagonist. Transl Psychiatry 8(1):84. https://doi.org/10.1038/s41398-018-0131-9
Grant ER, Bacskai BJ, Anegawa NJ, Pleasure DE, Lynch DR (1998) Opposing contributions of NR1 and NR2 to protein kinase C modulation of NMDA receptors. J Neurochem 71(4):1471–1481. https://doi.org/10.1046/j.1471-4159.1998.71041471.x
Gray JA, Shi Y, Usui H, During MJ, Sakimura K, Nicoll RA (2011) Distinct modes of AMPA receptor suppression at developing synapses by GluN2A and GluN2B: single-cell NMDA receptor subunit deletion in vivo. Neuron 71(6):1085–1101. https://doi.org/10.1016/j.neuron.2011.08.007
Green TL, Burket JA, Deutsch SI (2016) Age-dependent effects on social interaction of NMDA GluN2A receptor subtype-selective antagonism. Brain Res Bull 125:159–167. https://doi.org/10.1016/j.brainresbull.2016.06.017
Hackos DH, Lupardus PJ, Grand T, Chen Y, Wang TM, Reynen P, Gustafson A, Wallweber HJ, Volgraf M, Sellers BD, Schwarz JB, Paoletti P, Sheng M, Zhou Q, Hanson JE (2016) Positive allosteric modulators of GluN2A-containing NMDARs with distinct modes of action and impacts on circuit function. Neuron 89(5):983–999. https://doi.org/10.1016/j.neuron.2016.01.016
Hallett PJ, Dunah AW, Ravenscroft P, Zhou S, Bezard E, Crossman AR, Brotchie JM, Standaert DG (2005) Alterations of striatal NMDA receptor subunits associated with the development of dyskinesia in the MPTP-lesioned primate model of Parkinson’s disease. Neuropharmacology 48(4):503–516. https://doi.org/10.1016/j.neuropharm.2004.11.008
Hansen KB, Ogden KK, Traynelis SF (2012) Subunit-selective allosteric inhibition of glycine binding to NMDA receptors. J Neurosci 32(18):6197–6208. https://doi.org/10.1523/JNEUROSCI.5757-11.2012
Hansen KB, Ogden KK, Yuan H, Traynelis SF (2014) Distinct functional and pharmacological properties of triheteromeric GluN1/GluN2A/GluN2B NMDA receptors. Neuron 81(5):1084–1096. https://doi.org/10.1016/j.neuron.2014.01.035
Hanson JE, Ma K, Elstrott J, Weber M, Saillet S, Khan AS, Simms J, Liu B, Kim TA, Yu GQ, Chen Y, Wang TM, Jiang Z, Liederer BM, Deshmukh G, Solanoy H, Chan C, Sellers BD, Volgraf M, Schwarz JB, Hackos DH, Weimer RM, Sheng M, Gill TM, Scearce-Levie K, Palop JJ (2020) GluN2A NMDA receptor enhancement improves brain oscillations, synchrony, and cognitive functions in dravet syndrome and Alzheimer’s disease models. Cell Rep 30(2):381-396 e384. https://doi.org/10.1016/j.celrep.2019.12.030
Hatton CJ, Paoletti P (2005) Modulation of triheteromeric NMDA receptors by N-terminal domain ligands. Neuron 46(2):261–274. https://doi.org/10.1016/j.neuron.2005.03.005
He Y, Mu L, Ametamey SM, Schibli R (2019) Recent progress in allosteric modulators for GluN2A subunit and development of GluN2A-selective nuclear imaging probes. J Label Comp Radiopharm 62(8):552–560. https://doi.org/10.1002/jlcr.3744
Irvine MW, Fang G, Sapkota K, Burnell ES, Volianskis A, Costa BM, Culley G, Collingridge GL, Monaghan DT, Jane DE (2019) Investigation of the structural requirements for N-methyl-D-aspartate receptor positive and negative allosteric modulators based on 2-naphthoic acid. Eur J Med Chem 164:471–498. https://doi.org/10.1016/j.ejmech.2018.12.054
Ishihama K, Kogo M, Wakisaka S, Turman JE Jr (2005) Prenatal development of NMDA receptor composition and function in trigeminal neurons. Arch Histol Cytol 68(4):321–335. https://doi.org/10.1679/aohc.68.321
Itokawa M, Yamada K, Yoshitsugu K, Toyota T, Suga T, Ohba H, Watanabe A, Hattori E, Shimizu H, Kumakura T, Ebihara M, Meerabux JM, Toru M, Yoshikawa T (2003) A microsatellite repeat in the promoter of the N-methyl-D-aspartate receptor 2A subunit (GRIN2A) gene suppresses transcriptional activity and correlates with chronic outcome in schizophrenia. Pharmacogenetics 13(5):271–278. https://doi.org/10.1097/00008571-200305000-00006
Jalali-Yazdi F, Chowdhury S, Yoshioka C, Gouaux E (2018) Mechanisms for zinc and proton inhibition of the GluN1/GluN2A NMDA receptor. Cell 175(6):1520-1532 e1515. https://doi.org/10.1016/j.cell.2018.10.043
Jiang A, Su P, Li S, Wong AHC, Liu F (2021) Disrupting the alpha7nAChR-NR2A protein complex exerts antidepressant-like effects. Mol Brain 14(1):107. https://doi.org/10.1186/s13041-021-00817-3
Jimenez-Sanchez L, Campa L, Auberson YP, Adell A (2014) The role of GluN2A and GluN2B subunits on the effects of NMDA receptor antagonists in modeling schizophrenia and treating refractory depression. Neuropsychopharmacology 39(11):2673–2680. https://doi.org/10.1038/npp.2014.123
Karakas E, Simorowski N, Furukawa H (2011) Subunit arrangement and phenylethanolamine binding in GluN1/GluN2B NMDA receptors. Nature 475(7355):249–253. https://doi.org/10.1038/nature10180
Kinarsky L, Feng B, Skifter DA, Morley RM, Sherman S, Jane DE, Monaghan DT (2005) Identification of subunit- and antagonist-specific amino acid residues in the N-methyl-D-aspartate receptor glutamate-binding pocket. J Pharmacol Exp Ther 313(3):1066–1074. https://doi.org/10.1124/jpet.104.082990
Lai TKY, Zhai D, Su P, Jiang A, Boychuk J, Liu F (2019) The receptor-receptor interaction between mGluR1 receptor and NMDA receptor: a potential therapeutic target for protection against ischemic stroke. FASEB J 33(12):14423–14439. https://doi.org/10.1096/fj.201900417R
Laurie DJ, Seeburg PH (1994) Ligand affinities at recombinant N-methyl-D-aspartate receptors depend on subunit composition. Eur J Pharmacol 268(3):335–345. https://doi.org/10.1016/0922-4106(94)90058-2
Lee MC, Ting KK, Adams S, Brew BJ, Chung R, Guillemin GJ (2010) Characterisation of the expression of NMDA receptors in human astrocytes. PLoS ONE 5(11):e14123. https://doi.org/10.1371/journal.pone.0014123
Lei G, Liu F, Liu P, Jiao T, Yang L, Chu Z, Deng LS, Li Y, Dang YH (2020) Does genetic mouse model of constitutive Hint1 deficiency exhibit schizophrenia-like behaviors? Schizophr Res 222:304–318. https://doi.org/10.1016/j.schres.2020.05.018
Lemay-Clermont J, Robitaille C, Auberson YP, Bureau G, Cyr M (2011) Blockade of NMDA receptors 2A subunit in the dorsal striatum impairs the learning of a complex motor skill. Behav Neurosci 125(5):714–723. https://doi.org/10.1037/a0025213
Lin Y, Skeberdis VA, Francesconi A, Bennett MV, Zukin RS (2004) Postsynaptic density protein-95 regulates NMDA channel gating and surface expression. J Neurosci 24(45):10138–10148. https://doi.org/10.1523/JNEUROSCI.3159-04.2004
Lind GE, Mou TC, Tamborini L, Pomper MG, De Micheli C, Conti P, Pinto A, Hansen KB (2017) Structural basis of subunit selectivity for competitive NMDA receptor antagonists with preference for GluN2A over GluN2B subunits. Proc Natl Acad Sci U S A 114(33):E6942–E6951. https://doi.org/10.1073/pnas.1707752114
Ling W, Chang L, Song Y, Lu T, Jiang Y, Li Y, Wu Y (2012) Immunolocalization of NR1, NR2A, and PSD-95 in rat hippocampal subregions during postnatal development. Acta Histochem 114(3):285–295. https://doi.org/10.1016/j.acthis.2011.06.005
Liu L, Wong TP, Pozza MF, Lingenhoehl K, Wang Y, Sheng M, Auberson YP, Wang YT (2004) Role of NMDA receptor subtypes in governing the direction of hippocampal synaptic plasticity. Science 304(5673):1021–1024. https://doi.org/10.1126/science.1096615
Liu J, Chang L, Song Y, Li H, Wu Y (2019) The role of NMDA receptors in Alzheimer’s disease. Front Neurosci 13:43. https://doi.org/10.3389/fnins.2019.00043
Lu W, Du J, Goehring A, Gouaux E (2017) Cryo-EM structures of the triheteromeric NMDA receptor and its allosteric modulation. Science. https://doi.org/10.1126/science.aal3729
Luo J, Wang Y, Yasuda RP, Dunah AW, Wolfe BB (1997) The majority of N-methyl-D-aspartate receptor complexes in adult rat cerebral cortex contain at least three different subunits (NR1/NR2A/NR2B). Mol Pharmacol 51(1):79–86. https://doi.org/10.1124/mol.51.1.79
Mares P, Tsenov G, Kubova H (2021) Anticonvulsant action of GluN2A-preferring antagonist PEAQX in developing rats. Pharmaceutics. https://doi.org/10.3390/pharmaceutics13030415
Matas E, John Francis William D, Toro CT (2021) Abnormal expression of post-synaptic proteins in prefrontal cortex of patients with schizophrenia. Neurosci Lett 745:135629. https://doi.org/10.1016/j.neulet.2021.135629
Matta JA, Ashby MC, Sanz-Clemente A, Roche KW, Isaac JT (2011) mGluR5 and NMDA receptors drive the experience- and activity-dependent NMDA receptor NR2B to NR2A subunit switch. Neuron 70(2):339–351. https://doi.org/10.1016/j.neuron.2011.02.045
McKay S, Griffiths NH, Butters PA, Thubron EB, Hardingham GE, Wyllie DJ (2012) Direct pharmacological monitoring of the developmental switch in NMDA receptor subunit composition using TCN 213, a GluN2A-selective, glycine-dependent antagonist. Br J Pharmacol 166(3):924–937. https://doi.org/10.1111/j.1476-5381.2011.01748.x
Mellone M, Stanic J, Hernandez LF, Iglesias E, Zianni E, Longhi A, Prigent A, Picconi B, Calabresi P, Hirsch EC, Obeso JA, Di Luca M, Gardoni F (2015) NMDA receptor GluN2A/GluN2B subunit ratio as synaptic trait of levodopa-induced dyskinesias: from experimental models to patients. Front Cell Neurosci 9:245. https://doi.org/10.3389/fncel.2015.00245
Monaghan DT, Irvine MW, Costa BM, Fang G, Jane DE (2012) Pharmacological modulation of NMDA receptor activity and the advent of negative and positive allosteric modulators. Neurochem Int 61(4):581–592. https://doi.org/10.1016/j.neuint.2012.01.004
Monyer H, Burnashev N, Laurie DJ, Sakmann B, Seeburg PH (1994) Developmental and regional expression in the rat brain and functional properties of four NMDA receptors. Neuron 12(3):529–540. https://doi.org/10.1016/0896-6273(94)90210-0
Mota Vieira M, Nguyen TA, Wu K, Badger JD 2nd, Collins BM, Anggono V, Lu W, Roche KW (2020) An Epilepsy-associated GRIN2A rare variant disrupts CaMKIIalpha phosphorylation of GluN2A and NMDA receptor trafficking. Cell Rep 32(9):108104. https://doi.org/10.1016/j.celrep.2020.108104
Muller SL, Schreiber JA, Schepmann D, Strutz-Seebohm N, Seebohm G, Wunsch B (2017) Systematic variation of the benzenesulfonamide part of the GluN2A selective NMDA receptor antagonist TCN-201. Eur J Med Chem 129:124–134. https://doi.org/10.1016/j.ejmech.2017.02.018
Myers SJ, Yuan H, Kang JQ, Tan FCK, Traynelis SF, Low CM (2019) Distinct roles of GRIN2A and GRIN2B variants in neurological conditions. F1000Res. https://doi.org/10.12688/f1000research.18949.1
Neyton J, Paoletti P (2006) Relating NMDA receptor function to receptor subunit composition: limitations of the pharmacological approach. J Neurosci 26(5):1331–1333. https://doi.org/10.1523/JNEUROSCI.5242-05.2006
Nishi M, Hinds H, Lu HP, Kawata M, Hayashi Y (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
Pachernegg S, Strutz-Seebohm N, Hollmann M (2012) GluN3 subunit-containing NMDA receptors: not just one-trick ponies. Trends Neurosci 35(4):240–249. https://doi.org/10.1016/j.tins.2011.11.010
Pagano J, Giona F, Beretta S, Verpelli C, Sala C (2021) N-methyl-d-aspartate receptor function in neuronal and synaptic development and signaling. Curr Opin Pharmacol 56:93–101. https://doi.org/10.1016/j.coph.2020.12.006
Paoletti P (2011) Molecular basis of NMDA receptor functional diversity. Eur J Neurosci 33(8):1351–1365. https://doi.org/10.1111/j.1460-9568.2011.07628.x
Paoletti P, Bellone C, Zhou Q (2013) NMDA receptor subunit diversity: impact on receptor properties, synaptic plasticity and disease. Nat Rev Neurosci 14(6):383–400. https://doi.org/10.1038/nrn3504
Perez-Otano I, Schulteis CT, Contractor A, Lipton SA, Trimmer JS, Sucher NJ, Heinemann SF (2001) Assembly with the NR1 subunit is required for surface expression of NR3A-containing NMDA receptors. J Neurosci 21(4):1228–1237
Punnakkal P, Dominic D (2018) NMDA receptor GluN2 subtypes control epileptiform events in the hippocampus. Neuromolecular Med 20(1):90–96. https://doi.org/10.1007/s12017-018-8477-y
Rajan R, Schepmann D, Schreiber JA, Seebohm G, Wunsch B (2021a) Synthesis of GluN2A-selective NMDA receptor antagonists with an electron-rich aromatic B-ring. Eur J Med Chem 209:112939. https://doi.org/10.1016/j.ejmech.2020.112939
Rajan R, Schepmann D, Steigerwald R, Schreiber JA, El-Awaad E, Jose J, Seebohm G, Wunsch B (2021b) [2.2] Paracyclophane-based TCN-201 analogs as GluN2A-selective NMDA receptor antagonists. ChemMedChem. https://doi.org/10.1002/cmdc.202100400
Roberts AC, Diez-Garcia J, Rodriguiz RM, Lopez IP, Lujan R, Martinez-Turrillas R, Pico E, Henson MA, Bernardo DR, Jarrett TM, Clendeninn DJ, Lopez-Mascaraque L, Feng G, Lo DC, Wesseling JF, Wetsel WC, Philpot BD, Perez-Otano I (2009) Downregulation of NR3A-containing NMDARs is required for synapse maturation and memory consolidation. Neuron 63(3):342–356. https://doi.org/10.1016/j.neuron.2009.06.016
Romero-Hernandez A, Furukawa H (2017) Novel mode of antagonist binding in NMDA receptors revealed by the crystal structure of the GluN1-GluN2A ligand-binding domain complexed to NVP-AAM077. Mol Pharmacol 92(1):22–29. https://doi.org/10.1124/mol.116.107912
Romero-Hernandez A, Simorowski N, Karakas E, Furukawa H (2016) Molecular basis for subtype specificity and high-affinity zinc inhibition in the GluN1-GluN2A NMDA receptor amino-terminal domain. Neuron 92(6):1324–1336. https://doi.org/10.1016/j.neuron.2016.11.006
Rumbaugh G, Vicini S (1999) Distinct synaptic and extrasynaptic NMDA receptors in developing cerebellar granule neurons. J Neurosci 19(24):10603–10610
Sasaki YF, Rothe T, Premkumar LS, Das S, Cui J, Talantova MV, Wong HK, Gong X, Chan SF, Zhang D, Nakanishi N, Sucher NJ, Lipton SA (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. https://doi.org/10.1152/jn.00531.2001
Sheng M, Cummings J, Roldan LA, Jan YN, Jan LY (1994) Changing subunit composition of heteromeric NMDA receptors during development of rat cortex. Nature 368(6467):144–147. https://doi.org/10.1038/368144a0
Sitzia G, Mantas I, Zhang X, Svenningsson P, Chergui K (2020) NMDA receptors are altered in the substantia nigra pars reticulata and their blockade ameliorates motor deficits in experimental parkinsonism. Neuropharmacology 174:108136. https://doi.org/10.1016/j.neuropharm.2020.108136
Snyder MA, Gao WJ (2013) NMDA hypofunction as a convergence point for progression and symptoms of schizophrenia. Front Cell Neurosci 7:31. https://doi.org/10.3389/fncel.2013.00031
Stroebel D, Carvalho S, Paoletti P (2011) Functional evidence for a twisted conformation of the NMDA receptor GluN2A subunit N-terminal domain. Neuropharmacology 60(1):151–158. https://doi.org/10.1016/j.neuropharm.2010.07.003
Stroebel D, Casado M, Paoletti P (2018) Triheteromeric NMDA receptors: from structure to synaptic physiology. Curr Opin Physiol 2:1–12. https://doi.org/10.1016/j.cophys.2017.12.004
Summer SL, Kell SA, Zhu Z, Moore R, Liotta DC, Myers SJ, Koszalka GW, Traynelis SF, Menaldino DS (2019) Di-aryl sulfonamide motif adds pi-stacking bulk in negative allosteric modulators of the NMDA receptor. ACS Med Chem Lett 10(3):248–254. https://doi.org/10.1021/acsmedchemlett.8b00395
Sun Y, Chen Y, Zhan L, Zhang L, Hu J, Gao Z (2016) The role of non-receptor protein tyrosine kinases in the excitotoxicity induced by the overactivation of NMDA receptors. Rev Neurosci 27(3):283–289. https://doi.org/10.1515/revneuro-2015-0037
Sun Y, Cheng X, Zhang L, Hu J, Chen Y, Zhan L, Gao Z (2017) The functional and molecular properties, physiological functions, and pathophysiological roles of GluN2A in the central nervous system. Mol Neurobiol 54(2):1008–1021. https://doi.org/10.1007/s12035-016-9715-7
Sun Y, Cheng X, Hu J, Gao Z (2018a) The role of GluN2A in cerebral ischemia: promoting neuron death and Survival in the early stage and thereafter. Mol Neurobiol 55(2):1208–1216. https://doi.org/10.1007/s12035-017-0395-8
Sun Y, Xu Y, Cheng X, Chen X, Xie Y, Zhang L, Wang L, Hu J, Gao Z (2018b) The differences between GluN2A and GluN2B signaling in the brain. J Neurosci Res 96(8):1430–1443. https://doi.org/10.1002/jnr.24251
Takahashi T, Feldmeyer D, Suzuki N, Onodera K, Cull-Candy SG, Sakimura K, Mishina M (1996) Functional correlation of NMDA receptor epsilon subunits expression with the properties of single-channel and synaptic currents in the developing cerebellum. J Neurosci 16(14):4376–4382
Taniguchi S, Nakazawa T, Tanimura A, Kiyama Y, Tezuka T, Watabe AM, Katayama N, Yokoyama K, Inoue T, Izumi-Nakaseko H, Kakuta S, Sudo K, Iwakura Y, Umemori H, Inoue T, Murphy NP, Hashimoto K, Kano M, Manabe T, Yamamoto T (2009) Involvement of NMDAR2A tyrosine phosphorylation in depression-related behaviour. EMBO J 28(23):3717–3729. https://doi.org/10.1038/emboj.2009.300
Tong G, Takahashi H, Tu S, Shin Y, Talantova M, Zago W, Xia P, Nie Z, Goetz T, Zhang D, Lipton SA, Nakanishi N (2008) Modulation of NMDA receptor properties and synaptic transmission by the NR3A subunit in mouse hippocampal and cerebrocortical neurons. J Neurophysiol 99(1):122–132. https://doi.org/10.1152/jn.01044.2006
Traynelis SF, Wollmuth LP, McBain CJ, Menniti FS, Vance KM, Ogden KK, Hansen KB, Yuan H, Myers SJ, Dingledine R (2010) Glutamate receptor ion channels: structure, regulation, and function. Pharmacol Rev 62(3):405–496. https://doi.org/10.1124/pr.109.002451
Tseng WC, Reinhart V, Lanz TA, Weber ML, Pang J, Le KXV, Bell RD, O’Donnell P, Buhl DL (2021) Schizophrenia-associated SLC39A8 polymorphism is a loss-of-function allele altering glutamate receptor and innate immune signaling. Transl Psychiatry 11(1):136. https://doi.org/10.1038/s41398-021-01262-5
Vicini S, Wang JF, Li JH, Zhu WJ, Wang YH, Luo JH, Wolfe BB, Grayson DR (1998) Functional and pharmacological differences between recombinant N-methyl-D-aspartate receptors. J Neurophysiol 79(2):555–566. https://doi.org/10.1152/jn.1998.79.2.555
Villemure E, Volgraf M, Jiang Y, Wu G, Ly CQ, Yuen PW, Lu A, Luo X, Liu M, Zhang S, Lupardus PJ, Wallweber HJ, Liederer BM, Deshmukh G, Plise E, Tay S, Wang TM, Hanson JE, Hackos DH, Scearce-Levie K, Schwarz JB, Sellers BD (2017) GluN2A-selective pyridopyrimidinone series of NMDAR positive allosteric modulators with an improved in vivo profile. ACS Med Chem Lett 8(1):84–89. https://doi.org/10.1021/acsmedchemlett.6b00388
Volgraf M, Sellers BD, Jiang Y, Wu G, Ly CQ, Villemure E, Pastor RM, Yuen PW, Lu A, Luo X, Liu M, Zhang S, Sun L, Fu Y, Lupardus PJ, Wallweber HJ, Liederer BM, Deshmukh G, Plise E, Tay S, Reynen P, Herrington J, Gustafson A, Liu Y, Dirksen A, Dietz MG, Liu Y, Wang TM, Hanson JE, Hackos D, Scearce-Levie K, Schwarz JB (2016) Discovery of GluN2A-selective NMDA receptor positive allosteric modulators (PAMs): tuning deactivation kinetics via structure-based design. J Med Chem 59(6):2760–2779. https://doi.org/10.1021/acs.jmedchem.5b02010
Volkmann RA, Fanger CM, Anderson DR, Sirivolu VR, Paschetto K, Gordon E, Virginio C, Gleyzes M, Buisson B, Steidl E, Mierau SB, Fagiolini M, Menniti FS (2016) MPX-004 and MPX-007: new pharmacological tools to study the physiology of NMDA receptors containing the GluN2A subunit. PLoS ONE 11(2):e0148129. https://doi.org/10.1371/journal.pone.0148129
Williams K (1993) Ifenprodil discriminates subtypes of the N-methyl-D-aspartate receptor: selectivity and mechanisms at recombinant heteromeric receptors. Mol Pharmacol 44(4):851–859
Wu GM, Hou XY (2010) Oligomerized Abeta25-35 induces increased tyrosine phosphorylation of NMDA receptor subunit 2A in rat hippocampal CA1 subfield. Brain Res 1343:186–193. https://doi.org/10.1016/j.brainres.2010.04.055
Wu LJ, Xu H, Ren M, Cao X, Zhuo M (2007) Pharmacological isolation of postsynaptic currents mediated by NR2A- and NR2B-containing NMDA receptors in the anterior cingulate cortex. Mol Pain 3:11. https://doi.org/10.1186/1744-8069-3-11
Wyllie DJ, Livesey MR, Hardingham GE (2013) Influence of GluN2 subunit identity on NMDA receptor function. Neuropharmacology 74:4–17. https://doi.org/10.1016/j.neuropharm.2013.01.016
Xia CY, He J, Du LD, Yan Y, Lian WW, Xu JK, Zhang WK (2021) Targeting the dysfunction of glutamate receptors for the development of novel antidepressants. Pharmacol Ther 226:107875. https://doi.org/10.1016/j.pharmthera.2021.107875
Xiang Z, Conn PJ (2016) Novel PAMs Targeting NMDAR GluN2A Subunit. Neuron 89(5):884–886. https://doi.org/10.1016/j.neuron.2016.02.025
Xu XX, Liu XR, Fan CY, Lai JX, Shi YW, Yang W, Su T, Xu JY, Luo JH, Liao WP (2018) Functional investigation of a GRIN2A variant associated with rolandic epilepsy. Neurosci Bull 34(2):237–246. https://doi.org/10.1007/s12264-017-0182-6
Yi F, Mou TC, Dorsett KN, Volkmann RA, Menniti FS, Sprang SR, Hansen KB (2016) Structural basis for negative allosteric modulation of GluN2A-containing NMDA receptors. Neuron 91(6):1316–1329. https://doi.org/10.1016/j.neuron.2016.08.014
Zhang XM, Luo JH (2013) GluN2A versus GluN2B: twins, but quite different. Neurosci Bull 29(6):761–772. https://doi.org/10.1007/s12264-013-1336-9
Zhang JB, Chang S, Xu P, Miao M, Wu H, Zhang Y, Zhang T, Wang H, Zhang J, Xie C, Song N, Luo C, Zhang X, Zhu S (2018) Structural basis of the proton sensitivity of human GluN1-GluN2A NMDA receptors. Cell Rep 25(13):3582-3590 e3584. https://doi.org/10.1016/j.celrep.2018.11.071
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This work was supported by the natural science foundation of China (NSFC 81771265, 81903559, 82071333), the project of Hebei hundred talents plan (E2018100009), the high level talent funding program of Hebei province (A201901042), biological medicine joint fund of natural science foundation of Hebei Province (H2020208016, H2020208024, H2021208010), Scientific and Technical Research Foundation of the Higher Education Institutions of Hebei Province (ZD2017032) and open fund of Hebei technological innovation center of chiral medicine (ZXJJ20210205).
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YS, LW and CT put forward the idea and revised the work; MN drafted the work; XY revised the work; YL drafted the work; YS and LW performed the literature search and data analysis; JH, YX and ZG revised the work.
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Niu, M., Yang, X., Li, Y. et al. Progresses in GluN2A-containing NMDA Receptors and their Selective Regulators. Cell Mol Neurobiol 43, 139–153 (2023). https://doi.org/10.1007/s10571-021-01185-1
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DOI: https://doi.org/10.1007/s10571-021-01185-1