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Gene Review

Grin1  -  glutamate receptor, ionotropic, NMDA1...

Mus musculus

Synonyms: GluN1, GluRdelta1, GluRzeta1, Glurz1, Glutamate receptor ionotropic, NMDA 1, ...
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Disease relevance of Grin1


Psychiatry related information on Grin1

  • Barrel cortex critical period plasticity is independent of changes in NMDA receptor subunit composition [6].
  • The biochemical processes underlying opiate addiction are complex, but n-methyl-d-aspartate receptor (NMDAR) dysfunction appears to be one contributing factor [7].
  • ABSTRACT : BACKGROUND : The Ca2+/calmodulin-stimulated adenylyl cyclase (AC) isoforms AC1 and AC8, couple NMDA receptor activation to cAMP signaling pathways in neurons and are important for development, learning and memory, drug addiction and persistent pain [8].
  • Unlike NR1 null mice, these mice survive to adulthood and display behavioral abnormalities, including increased motor activity and stereotypy and deficits in social and sexual interactions [9].
  • Enrichment induces structural changes and recovery from nonspatial memory deficits in CA1 NMDAR1-knockout mice [10].

High impact information on Grin1

  • Moreover, in Eps8 null mice, NMDA receptor currents and their sensitivity to inhibition by ethanol are abnormal [11].
  • These findings support a model in which reduced NMDA receptor activity results in schizophrenic-like behavior and reveals how pharmacological manipulation of monoaminergic pathways can affect this phenotype [9].
  • Ablation of cerebellar Golgi cells disrupts synaptic integration involving GABA inhibition and NMDA receptor activation in motor coordination [12].
  • We have produced a mouse strain in which the deletion of the NMDAR1 gene is restricted to the CA1 pyramidal cells of the hippocampus by using a new and general method that allows CA1-restricted gene knockout [13].
  • Adult mice lack NMDA receptor-mediated synaptic currents and long-term potentiation in the CA1 synapses and exhibit impaired spatial memory but unimpaired nonspatial learning [13].

Chemical compound and disease context of Grin1


Biological context of Grin1


Anatomical context of Grin1

  • By using a knockout mouse strain, in which the NR1 gene deletion is primarily targeted to the CA1 pyramidal cells of the hippocampus, we investigated the in vivo effect of the loss of the NR1 subunit on the cellular expression and intracellular distribution of the NR2 subunits [23].
  • These granules were also observed in CA1 pyramidal cells of the control mice but they were much fewer and contained no detectable levels of the NR2 subunit [23].
  • This reduced dendritic distribution of the NR2 subunits accompanied their robust accumulation in perikarya, where they were condensed in the lumen of the endoplasmic reticulum as electron-dense granules [23].
  • Triton X-100/1 M NaCl-solubilised forebrain NMDA receptors had a molecular size of 710,000 daltons, but significant NR1 immunoreactivity (41%) migrated as a monomer of 125,000 daltons [24].
  • Thus the involvement of PTPalpha as an upstream regulator of NMDAR tyrosine phosphorylation was investigated in synaptosomes of wild-type and PTPalpha-null mice [25].

Associations of Grin1 with chemical compounds

  • Targeted disruption of NMDA receptor 1 gene abolishes NMDA response and results in neonatal death [22].
  • In order to study the role of tyrosine kinase signaling in the post-synaptic density (PSD), tyrosine-phosphorylated proteins associated with the PSD-95/NMDA receptor complex were analyzed [26].
  • The NMDA receptor complex from the mouse brain was successfully solubilized with deoxycholate and immunopurified with anti-PSD-95 or anti-phosphotyrosine antibody [26].
  • Using these cells, we observed that the neuroactive steroid, pregnenolone sulfate (PREGS), is able to stimulate the release of GnRH in a dose-dependent manner through N-methyl-D-aspartate (NMDA) receptors, because its action is completely blocked by a specific NMDA receptor antagonist and magnesium [27].
  • These results are consistent with the identification of a pool of unassembled C2 exon-containing NR1 subunits, i.e., NR1-1a, NR1-1b, NR1-2a, and NR1-2b, selectively solubilised by 1% Triton X-100/1 M NaCl [24].

Physical interactions of Grin1

  • Immunoblot analyses revealed that the predominantly tyrosine-phosphorylated proteins in the NMDA receptor complex are the NR2A/B subunits and a novel 120 kDa protein [26].
  • A similar redistribution pattern in the ipsilateral AVCN for the N-methyl-D-aspartate (NMDA) receptor was also observed at POD 4, corresponding to the fact that the activation of nNOS is coupled to calcium influx via the NMDA-receptor [28].
  • By using the yeast two-hybrid system, we found that calmodulin interacts with the COOH terminus of the NR1 subunit and inactivates the channels in a Ca2+-dependent manner [29].
  • These results confirm the observations obtained with other basic molecules and suggest that the behavior induced by poly-l-lysine is mediated through the activation of the NMDA receptor ion-channel complex acting either on the polyamine recognition site or on the NR2B subunit [30].
  • After investigating the effect of coactivation of the NMDAR and the Gs-coupled beta-adrenergic receptor on GluR1 phosphorylation state, we have observed a novel signal that prevents PKA-mediated phosphorylation of GluR1 at serine site 845 [31].

Enzymatic interactions of Grin1


Co-localisations of Grin1

  • We report here that PSD-93 colocalizes and interacts with the NMDA receptor and neuronal nitric oxide synthase in cultured cortical neurons [34].

Regulatory relationships of Grin1

  • In conclusion, NT-3 regulates the expression of NMDAR subunits modifying striatal neuronal properties that confers the differential vulnerability to excitotoxicity in projection neurons and interneurons in the striatum [35].
  • Thus, the NMDA-R protein level is regulated by the Reelin protein level in a Fyn-dependent manner in the mouse brain [36].
  • Consistent with these results, immunocytochemistry revealed that NR1-expressing neurons also expressed ApoER2 and VLDLR [37].
  • The maturation-induced change in NMDAR subunits also was blocked by chronic treatment with an inhibitor of the Src kinase signaling pathway or an antagonist of the LDL receptors, but not by inhibitors of another class of Reelin receptor belonging to the integrin family [37].
  • Early postnatal developmental changes in N-methyl-d-aspartate (NMDA) receptor (NR) subunits regulate cerebellar granule cell maturation and potentially Purkinje cell development [38].

Other interactions of Grin1

  • A concomitant reduction in levels of NR2B but not NR2A occurred in NR1-/- mice, demonstrating that there is an interdependence of subunit expression [22].
  • In the current study, we explored visual cortex plasticity and NMDAR function in NR2B overexpressing transgenic mice [39].
  • Western blots analysis showed a trend of reduction in AMPA and NMDA receptor subunits, mainly GluR1 and NR2A, exclusively in the cervical region of late symptomatic mice in the triton-insoluble post-synaptic fraction but not whole homogenates [3].
  • Furthermore, mice lacking PSD-93 exhibit blunted NMDAR-dependent persistent pain induced by peripheral nerve injury or injection of Complete Freund's Adjuvant, although they display intact nociceptive responsiveness to acute pain [40].
  • However, we could find no difference in the properties of NMDAR-mediated EPSCs between wild-type and NR2D subunit ablated mice [41].

Analytical, diagnostic and therapeutic context of Grin1

  • The most potent NMDA receptor antagonists [(+)-2, (-)-4, and (+)-5] showed a significant neuroprotective effect when tested in an oxygen glucose deprivation (OGD) cell culture test [42].
  • In the present study, we used immunohistochemistry to examine the distribution of NMDA receptor subunits in the adult mouse cerebellum [43].
  • METHODS: In situ hybridization of riboprobes was used to characterize NMDA receptor subunit and splice variant mRNA expression in cortex and hippocampus from WSP and WSR mice [44].
  • Results from Western blot and immunohistochemical experiments also indicated that there were no differences between selected lines in NMDA receptor subunit protein expression [44].
  • However, the mRNA levels of the NMDA-R subunits, determined by quantitative RT-PCR, were the same as in wild-type mice [36].


  1. Attenuation of focal ischemic brain injury in mice deficient in the epsilon1 (NR2A) subunit of NMDA receptor. Morikawa, E., Mori, H., Kiyama, Y., Mishina, M., Asano, T., Kirino, T. J. Neurosci. (1998) [Pubmed]
  2. Dopamine D1-dependent trafficking of striatal N-methyl-D-aspartate glutamate receptors requires Fyn protein tyrosine kinase but not DARPP-32. Dunah, A.W., Sirianni, A.C., Fienberg, A.A., Bastia, E., Schwarzschild, M.A., Standaert, D.G. Mol. Pharmacol. (2004) [Pubmed]
  3. Expression of AMPA and NMDA receptor subunits in the cervical spinal cord of wobbler mice. Bigini, P., Gardoni, F., Barbera, S., Cagnotto, A., Fumagalli, E., Longhi, A., Corsi, M.M., Di Luca, M., Mennini, T. BMC neuroscience (2006) [Pubmed]
  4. Translational regulation of the N-methyl-D-aspartate receptor subunit NR1. Vazhappilly, R., Sucher, N.J. Neurosignals (2004) [Pubmed]
  5. Functional characterization of a heteromeric NMDA receptor channel expressed from cloned cDNAs. Meguro, H., Mori, H., Araki, K., Kushiya, E., Kutsuwada, T., Yamazaki, M., Kumanishi, T., Arakawa, M., Sakimura, K., Mishina, M. Nature (1992) [Pubmed]
  6. Barrel cortex critical period plasticity is independent of changes in NMDA receptor subunit composition. Lu, H.C., Gonzalez, E., Crair, M.C. Neuron (2001) [Pubmed]
  7. Conantokins and variants derived from cone snail venom inhibit naloxone-induced withdrawal jumping in morphine-dependent mice. Wei, J., Dong, M., Xiao, C., Jiang, F., Castellino, F.J., Prorok, M., Dai, Q. Neurosci. Lett. (2006) [Pubmed]
  8. Genetic reduction of chronic muscle pain in mice lacking calcium/calmodulin-stimulated adenylyl cyclases. Vadakkan, K.I., Wang, H., Ko, S.W., Zastepa, E., Petrovic, M.J., Sluka, K.A., Zhuo, M. Molecular pain [electronic resource] (2006) [Pubmed]
  9. Mice with reduced NMDA receptor expression display behaviors related to schizophrenia. Mohn, A.R., Gainetdinov, R.R., Caron, M.G., Koller, B.H. Cell (1999) [Pubmed]
  10. Enrichment induces structural changes and recovery from nonspatial memory deficits in CA1 NMDAR1-knockout mice. Rampon, C., Tang, Y.P., Goodhouse, J., Shimizu, E., Kyin, M., Tsien, J.Z. Nat. Neurosci. (2000) [Pubmed]
  11. Increased ethanol resistance and consumption in eps8 knockout mice correlates with altered actin dynamics. Offenh??user, N., Castelletti, D., Mapelli, L., Soppo, B.E., Regondi, M.C., Rossi, P., D'Angelo, E., Frassoni, C., Amadeo, A., Tocchetti, A., Pozzi, B., Disanza, A., Guarnieri, D., Betsholtz, C., Scita, G., Heberlein, U., Di Fiore, P.P. Cell (2006) [Pubmed]
  12. Ablation of cerebellar Golgi cells disrupts synaptic integration involving GABA inhibition and NMDA receptor activation in motor coordination. Watanabe, D., Inokawa, H., Hashimoto, K., Suzuki, N., Kano, M., Shigemoto, R., Hirano, T., Toyama, K., Kaneko, S., Yokoi, M., Moriyoshi, K., Suzuki, M., Kobayashi, K., Nagatsu, T., Kreitman, R.J., Pastan, I., Nakanishi, S. Cell (1998) [Pubmed]
  13. The essential role of hippocampal CA1 NMDA receptor-dependent synaptic plasticity in spatial memory. Tsien, J.Z., Huerta, P.T., Tonegawa, S. Cell (1996) [Pubmed]
  14. Distribution of alpha-amino-3-hydroxy-5-methyl-4 isoazolepropionic acid and N-methyl-D-aspartate receptor subunits in the vestibular and spiral ganglia of the mouse during early development. Puyal, J., Sage, C., Demêmes, D., Dechesne, C.J. Brain Res. Dev. Brain Res. (2002) [Pubmed]
  15. Specific coupling of NMDA receptor activation to nitric oxide neurotoxicity by PSD-95 protein. Sattler, R., Xiong, Z., Lu, W.Y., Hafner, M., MacDonald, J.F., Tymianski, M. Science (1999) [Pubmed]
  16. Neuropathic sensitization of behavioral reflexes and spinal NMDA receptor/CaM kinase II interactions are disrupted in PSD-95 mutant mice. Garry, E.M., Moss, A., Delaney, A., O'Neill, F., Blakemore, J., Bowen, J., Husi, H., Mitchell, R., Grant, S.G., Fleetwood-Walker, S.M. Curr. Biol. (2003) [Pubmed]
  17. Stimulation of adenosine A2A receptors elicits zif/268 and NMDA epsilon2 subunit mRNA expression in cortex and striatum of the "weaver" mutant mouse, a genetic model of nigrostriatal dopamine deficiency. Ekonomou, A., Poulou, P.D., Matsokis, N., Angelatou, F. Neuroscience (2004) [Pubmed]
  18. NMDA and AMPA glutamate receptor subtypes in the thoracic spinal cord in lean and obese-diabetic ob/ob mice. Li, N., Young, M.M., Bailey, C.J., Smith, M.E. Brain Res. (1999) [Pubmed]
  19. Functional consequences of reduction in NMDA receptor glycine affinity in mice carrying targeted point mutations in the glycine binding site. Kew, J.N., Koester, A., Moreau, J.L., Jenck, F., Ouagazzal, A.M., Mutel, V., Richards, J.G., Trube, G., Fischer, G., Montkowski, A., Hundt, W., Reinscheid, R.K., Pauly-Evers, M., Kemp, J.A., Bluethmann, H. J. Neurosci. (2000) [Pubmed]
  20. Reduced hippocampal LTP and spatial learning in mice lacking NMDA receptor epsilon 1 subunit. Sakimura, K., Kutsuwada, T., Ito, I., Manabe, T., Takayama, C., Kushiya, E., Yagi, T., Aizawa, S., Inoue, Y., Sugiyama, H. Nature (1995) [Pubmed]
  21. NMDA receptors regulate developmental gap junction uncoupling via CREB signaling. Arumugam, H., Liu, X., Colombo, P.J., Corriveau, R.A., Belousov, A.B. Nat. Neurosci. (2005) [Pubmed]
  22. Targeted disruption of NMDA receptor 1 gene abolishes NMDA response and results in neonatal death. Forrest, D., Yuzaki, M., Soares, H.D., Ng, L., Luk, D.C., Sheng, M., Stewart, C.L., Morgan, J.I., Connor, J.A., Curran, T. Neuron (1994) [Pubmed]
  23. Retention of NMDA receptor NR2 subunits in the lumen of endoplasmic reticulum in targeted NR1 knockout mice. Fukaya, M., Kato, A., Lovett, C., Tonegawa, S., Watanabe, M. Proc. Natl. Acad. Sci. U.S.A. (2003) [Pubmed]
  24. Biochemical evidence for the existence of a pool of unassembled C2 exon-containing NR1 subunits of the mammalian forebrain NMDA receptor. Chazot, P.L., Stephenson, F.A. J. Neurochem. (1997) [Pubmed]
  25. Reduced NMDA receptor tyrosine phosphorylation in PTPalpha-deficient mouse synaptosomes is accompanied by inhibition of four src family kinases and Pyk2: an upstream role for PTPalpha in NMDA receptor regulation. Le, H.T., Maksumova, L., Wang, J., Pallen, C.J. J. Neurochem. (2006) [Pubmed]
  26. Identification of PSD-93 as a substrate for the Src family tyrosine kinase Fyn. Nada, S., Shima, T., Yanai, H., Husi, H., Grant, S.G., Okada, M., Akiyama, T. J. Biol. Chem. (2003) [Pubmed]
  27. The neuroactive steroid pregnenolone sulfate stimulates the release of gonadotropin-releasing hormone from GT1-7 hypothalamic neurons, through N-methyl-D-aspartate receptors. El-Etr, M., Akwa, Y., Baulieu, E.E., Schumacher, M. Endocrinology (2006) [Pubmed]
  28. Co-induction of growth-associated protein GAP-43 and neuronal nitric oxide synthase in the cochlear nucleus following cochleotomy. Chen, T.J., Huang, C.W., Wang, D.C., Chen, S.S. Experimental brain research. Experimentelle Hirnforschung. Expérimentation cérébrale. (2004) [Pubmed]
  29. Phosphorylation-dependent regulation of N-methyl-D-aspartate receptors by calmodulin. Hisatsune, C., Umemori, H., Inoue, T., Michikawa, T., Kohda, K., Mikoshiba, K., Yamamoto, T. J. Biol. Chem. (1997) [Pubmed]
  30. Nociceptive behavior induced by poly-L-lysine and other basic compounds involves the spinal NMDA receptors. Tan-No, K., Esashi, A., Nakagawasai, O., Niijima, F., Sakurada, C., Sakurada, T., Bakalkin, G., Terenius, L., Tadano, T. Brain Res. (2004) [Pubmed]
  31. Novel blockade of protein kinase A-mediated phosphorylation of AMPA receptors. Vanhoose, A.M., Clements, J.M., Winder, D.G. J. Neurosci. (2006) [Pubmed]
  32. Analysis of NMDA receptor mediated synaptic plasticity using gene targeting: roles of Fyn and FAK non-receptor tyrosine kinases. Grant, S.G. J. Physiol. Paris (1996) [Pubmed]
  33. NMDA-dependent proteolysis of presynaptic adhesion molecule L1 in the hippocampus by neuropsin. Matsumoto-Miyai, K., Ninomiya, A., Yamasaki, H., Tamura, H., Nakamura, Y., Shiosaka, S. J. Neurosci. (2003) [Pubmed]
  34. Targeted disruption of PSD-93 gene reduces platelet-activating factor-induced neurotoxicity in cultured cortical neurons. Xu, Y., Zhang, B., Hua, Z., Johns, R.A., Bredt, D.S., Tao, Y.X. Exp. Neurol. (2004) [Pubmed]
  35. Mice heterozygous for neurotrophin-3 display enhanced vulnerability to excitotoxicity in the striatum through increased expression of N-methyl-d-aspartate receptors. Torres-Peraza, J., Pezzi, S., Canals, J.M., Gavald??, N., Garc??a-Mart??nez, J.M., P??rez-Navarro, E., Alberch, J. Neuroscience (2007) [Pubmed]
  36. NMDA-receptor proteins are upregulated in the hippocampus of postnatal heterozygous reeler mice. Isosaka, T., Hattori, K., Yagi, T. Brain Res. (2006) [Pubmed]
  37. Reelin, very-low-density lipoprotein receptor, and apolipoprotein E receptor 2 control somatic NMDA receptor composition during hippocampal maturation in vitro. Sinagra, M., Verrier, D., Frankova, D., Korwek, K.M., Blahos, J., Weeber, E.J., Manzoni, O.J., Chavis, P. J. Neurosci. (2005) [Pubmed]
  38. Lack of NMDA receptor subunit exchange alters Purkinje cell dendritic morphology in cerebellar slice cultures. Metzger, F., Pieri, I., Eisel, U.L. Brain Res. Dev. Brain Res. (2005) [Pubmed]
  39. Effect of transgenic overexpression of NR2B on NMDA receptor function and synaptic plasticity in visual cortex. Philpot, B.D., Weisberg, M.P., Ramos, M.S., Sawtell, N.B., Tang, Y.P., Tsien, J.Z., Bear, M.F. Neuropharmacology (2001) [Pubmed]
  40. Impaired NMDA receptor-mediated postsynaptic function and blunted NMDA receptor-dependent persistent pain in mice lacking postsynaptic density-93 protein. Tao, Y.X., Rumbaugh, G., Wang, G.D., Petralia, R.S., Zhao, C., Kauer, F.W., Tao, F., Zhuo, M., Wenthold, R.J., Raja, S.N., Huganir, R.L., Bredt, D.S., Johns, R.A. J. Neurosci. (2003) [Pubmed]
  41. NR2B and NR2D subunits coassemble in cerebellar Golgi cells to form a distinct NMDA receptor subtype restricted to extrasynaptic sites. Brickley, S.G., Misra, C., Mok, M.H., Mishina, M., Cull-Candy, S.G. J. Neurosci. (2003) [Pubmed]
  42. Synthesis, binding affinity at glutamic acid receptors, neuroprotective effects, and molecular modeling investigation of novel dihydroisoxazole amino acids. Conti, P., De Amici, M., Grazioso, G., Roda, G., Pinto, A., Hansen, K.B., Nielsen, B., Madsen, U., Bräuner-Osborne, H., Egebjerg, J., Vestri, V., Pellegrini-Giampietro, D.E., Sibille, P., Acher, F.C., De Micheli, C. J. Med. Chem. (2005) [Pubmed]
  43. NMDA receptor subunits GluRepsilon1, GluRepsilon3 and GluRzeta1 are enriched at the mossy fibre-granule cell synapse in the adult mouse cerebellum. Yamada, K., Fukaya, M., Shimizu, H., Sakimura, K., Watanabe, M. Eur. J. Neurosci. (2001) [Pubmed]
  44. NMDA receptor subunit mRNA and protein expression in ethanol-withdrawal seizure-prone and -resistant mice. Mason, J.N., Eshleman, A.J., Belknap, J.K., Crabbe, J.C., Loftis, J.M., Macey, T.A., Janowsky, A. Alcohol. Clin. Exp. Res. (2001) [Pubmed]
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