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GRIN1  -  glutamate receptor, ionotropic, N-methyl D...

Homo sapiens

Synonyms: GluN1, Glutamate receptor ionotropic, NMDA 1, MRD8, N-methyl-D-aspartate receptor subunit NR1, NMD-R1, ...
 
 
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Disease relevance of GRIN1

 

Psychiatry related information on GRIN1

 

High impact information on GRIN1

  • Antagonists of N-methyl-D-aspartate (NMDA) channels or voltage-gated Na(+) or certain types of Ca(2+) channels can postpone or mitigate SD or HSD, but it takes a combination of drugs blocking all known major inward currents to effectively prevent HSD [10].
  • Furthermore, caspase-6-resistant mutant htt mice are protected against neurotoxicity induced by multiple stressors including NMDA, quinolinic acid (QA), and staurosporine [11].
  • Here, we report that dopamine D1 receptors modulate NMDA glutamate receptor-mediated functions through direct protein-protein interactions [12].
  • We find that EphrinB binding to EphB induces a direct interaction of EphB with NMDA-type glutamate receptors [13].
  • Optical and electrical recordings combined with immunocytological analysis indicated that elimination of Golgi cells not only reduces GABA-mediated inhibition but also attenuates functional NMDA receptors in granule cells [14].
 

Chemical compound and disease context of GRIN1

  • To evaluate the role of protein kinase C (PKC) activation in NMDA-mediated toxicity, we have analyzed the survival of transfected HEK cells using trypan blue exclusion [15].
  • The present study demonstrates that human SK-N-SH neuroblastoma cells, differentiated by retinoic acid (RA), express functional NMDA receptors and become vulnerable to glutamate toxicity [16].
  • The atypical antagonist ifenprodil inhibited toxicity with a uniformly high affinity characteristic of interaction with the NR1-NR2B combination of subunits [17].
  • Such treatment markedly suppressed NMDA receptor activity: at 8 days in vitro NMDA-induced 45Ca2+ influx was reduced by approximately 60% and acute exposure to NMDA (highest concentration tested, 1 mM) at 9 days in vitro did not cause detectable toxicity [18].
  • To investigate the possibility that felbamate's favorable toxicity profile could be related to NMDA receptor subtype selectivity, we examined the specificity of felbamate block of recombinant NMDA receptors composed of the NR1a subunit and various NR2 subunits [19].
 

Biological context of GRIN1

  • We tested for the presence of linkage disequilibrium between the GRIN1 (1001-G/C, 1970-A/G, and 6608-G/C polymorphisms) and BP [5].
  • These findings suggest that the combined effects of the polymorphisms in the GRIN1 and GRIN2B genes might be involved in the etiology of schizophrenia.European Journal of Human Genetics (2005) 13, 807-814. doi:10.1038/sj.ejhg.5201418 Published online 20 April 2005 [20].
  • We tested the hypothesis that GRIN1 polymorphisms were associated with schizophrenia using the transmission disequilibrium test (TDT) and comparing allele frequencies between cases and controls [21].
  • Activation of the N-methyl-D-aspartate (NMDA) receptor is important for certain forms of activity-dependent synaptic plasticity, such as long-term potentiation (reviewed in ref. 1), and the patterning of connections during development of the visual system (reviewed in refs 2, 3) [22].
  • We used partial agonists at the glutamate and glycine binding sites to show that at least two kinetically distinct subunit-associated conformational changes link co-agonist binding to the opening of the NMDA receptor pore [23].
 

Anatomical context of GRIN1

 

Associations of GRIN1 with chemical compounds

  • The N-methyl D-aspartate (NMDA) receptor subtype of glutamate-gated ion channels possesses high calcium permeability and unique voltage-dependent sensitivity to magnesium and is modulated by glycine [24].
  • We also show a similar interaction between the ifenprodil binding site and the glutamate binding site of NR1/NR2B receptors [28].
  • In cells expressing the NR1-NR2B, -NR2C, and -NR2D channels DTT elicited only a slowly developing, persistent potentiation and increased the deactivation time course [29].
  • A set of arginine-rich hexapeptides selectively blocked the NMDA receptor channel with IC50 approximately 100 nM, a potency similar to clinically tolerated blockers such as memantine, and only marginally blocked on non-NMDA glutamate receptors [26].
  • The rapidly triggered excitotoxicity induced by glutamate was blocked by NMDA selective antagonists, was calcium dependent and pH sensitive and could be mimicked by NMDA but not by non-NMDA agonists, AMPA, kainate or quisqualate [1].
 

Physical interactions of GRIN1

  • Calcium-calmodulin-dependent protein kinase II phosphorylation modulates PSD-95 binding to NMDA receptors [30].
  • Additional clustering of NMDA receptors is provided through the binding of NRI subunits to the cytoskeletal protein alpha-actinin-2 [31].
  • Tiam1 interacts with the NMDA receptor and is phosphorylated in a calcium-dependent manner in response to NMDA receptor stimulation [32].
  • When depolarized, cortical neurons release bio-active t-PA that interacts with and cleaves the NR1 subunit of the NMDA receptor [33].
  • We have localized regions in the S1 binding domain of both subunits required for the transmission of allosteric signals from the glutamate binding NR2A subunit to the glycine binding NR1 subunit [34].
 

Regulatory relationships of GRIN1

  • Here, we demonstrate that CaMKIIalpha enhances the extent and/or rate of desensitization of NMDA-induced macroscopic currents in HEK293 cells co-expressing NR2B with either the NR1(011) or NR1(101) splice variants, without significantly changing other current parameters [35].
  • PSD-95 and PKC each enhance NMDA channel activity, with no change in single-channel conductance, reversal potential or mean open time [36].
  • The protein tyrosine kinase Src is known to regulate NMDA receptors in native neurons [37].
  • Interleukin-2 inhibits NMDA receptor-mediated currents directly and may differentially affect subtypes [38].
  • In contrast to the null effects of con-G and Ala/con-G at a NR1a/NR2A-containing receptor, some inhibition ( approximately 40%) of NMDA-evoked currents was effected by these peptides in cells expressing NR1b/NR2A [39].
 

Other interactions of GRIN1

  • Furthermore, non-HS hippocampi showed increased NR1 and NR2B mRNA levels per CA2/3 pyramidal neuron compared with autopsy cases [40].
  • HS patients, by comparison, showed decreased pyramidal neuron NR2A mRNA levels, and this suggests that NMDA-mediated pyramidal neuron responses should be reduced in HS patients compared with non-HS cases [40].
  • By contrast, the cerebellar cortex of both schizophrenics and controls contained very high levels of NR2C subunit mRNA, whereas levels for the other subunit mRNAs were very low, except NR1, for which levels were moderate [27].
  • The results suggest that native NMDA receptors containing the NR2D subunit may have functional roles not only in the young brain but also in adult brain [41].
  • PSD-95 and PKC each increase NMDAR surface expression, as indicated by immunofluorescence [36].
 

Analytical, diagnostic and therapeutic context of GRIN1

  • Hippocampal sclerosis (HS; n = 16), non-HS (n = 10), and autopsy hippocampi (n = 9) were studied for NMDAR1 (NR1) and NR2A-D mRNA levels by using semiquantitative in situ hybridization techniques, along with neuron densities [40].
  • Immunoblotting of the double immunopurified NR2A/NR2B(FLAG)-containing material demonstrated the presence of anti-NR1, anti-NR2A, anti-FLAG, and, more important, anti-c-Myc antibody immunoreactivities [42].
  • High affinity sites for CGP 61594 were exclusively displayed by NR1/2B receptors, as shown by their co-distribution with the NR2B subunit, by subunit-selective immunoprecipitation and by functional analysis of NR1/2B receptors expressed in Xenopus oocytes (inhibitory potency, IC50 = 45 +/- 11 nM) [43].
  • The NMDA receptor complex is altered in an animal model of human cerebral heterotopia [44].
  • We examined inactivation in heteromeric NMDA receptors expressed in human embryonic kidney (HEK) 293 cells using whole-cell recording [45].

References

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  14. 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]
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  18. Agonist-induced down-regulation of NMDA receptors in cerebellar granule cells in culture. Resink, A., Villa, M., Boer, G.J., Möhler, H., Balázs, R. Eur. J. Neurosci. (1995) [Pubmed]
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