Disease relevance of Grin1

• The N-methyl-D-aspartate subtype of glutamate receptor (NMDAR) serves critical functions in physiological and pathological processes in the central nervous system, including neuronal development, plasticity and neurodegeneration [1].
• Using cultured rat cerebellar granule cells, we investigated whether BDNF and FGF2 prevent NMDA toxicity by downregulating NMDA receptor function [2].
• We examined changes in GnRH and NMDA-R1 gene expression by RNase protection assay of preoptic area-anterior hypothalamic (POA-AH) dissections of female rats undergoing normal puberty or in which precocious puberty was induced by treatment with the glutamate agonist NMA [3].
• A similar mechanism of autoregulation of the receptor probably operates during cerebral ischemia, because NR1 mRNA and protein were strongly decreased at early stages of blood reperfusion in the infarcted brains of rats subjected to occlusion of the middle cerebral artery [4].
• Ischemic preconditioning selectively induces a decrease in the levels of the NR2A and NR2B subunits and a modest decrease in the levels of NR1 subunit proteins in the synaptosomal fraction of the neocortex but not hippocampus after the second lethal ischemia [5].

Psychiatry related information on Grin1

• Taking together, these findings suggested that NR2B containing NMDA receptor may be more involved with morphine reward rather than natural rewards, and that antagonism of NR2B may have a potential for the treatment of morphine abuse [6].
• (2) Ifenprodil, an antagonist highly selective for NR2B subunit of the NMDA receptor, produced a dose-dependent reduction in CPP induced by morphine and novel environment, but not that by food consumption and social interaction [6].
• The transient changes in NR1 and the NR2C subunit mRNA expressions in response to sensory deprivation are consistent with an active role for NMDA receptors in the appearance and development of the vestibular compensatory process [7].
• The ability of these NMDA receptor antagonists to disrupt the prepulse inhibition (PPI) of the startle response and to alter locomotor activity was also studied [8].
• The results show that chronic intraventricular infusion of the NMDA receptor antagonist D,L-2-amino-5-phosphonopentanoic acid (D,L-AP5) caused an impairment of spatial but not of visual discrimination learning in rats [9].

High impact information on Grin1

• The rapid scaling induced by NMDAR mini blockade is mediated by increased synaptic expression of surface GluR1 and the transient incorporation of Ca2+-permeable AMPA receptors at synapses; both of these changes are implemented locally within dendrites and require dendritic protein synthesis [10].
• These results indicate that NMDAR signaling during miniature synaptic transmission serves to stabilize synaptic function through active suppression of dendritic protein synthesis [10].
• Consequently, the degree of astrocytic coverage of neurons governs the level of glycine site occupancy on the NMDA receptor, thereby affecting their availability for activation and thus the activity dependence of long-term synaptic changes [11].
• Glia-derived D-serine controls NMDA receptor activity and synaptic memory [11].
• (2006) show that D-serine released by astrocytes, a type of glial cell in the brain, promotes NMDA receptor activity at synapses in the hypothalamus [12].

Chemical compound and disease context of Grin1

• Increase in tyrosine phosphorylation of the NMDA receptor following the induction of status epilepticus [13].
• Recent work has shown substantial alterations in NMDA receptor subunit expression, assembly, and phosphorylation in the dopamine-depleted striatum of a rodent 6-hydroxydopamine model of Parkinson's disease [14].
• In contrast, reactive microglia expressed GluR4 and NR1 subunits, alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA), and NMDA receptor subtypes, respectively, with maximal expression observed between 3 and 7 days after ischemia [15].
• Block of the channel of N-methyl-D-aspartate (NMDA) receptors by external Mg(2+) (Mg(o)(2+)) has broad implications for the many physiological and pathological processes that depend on NMDA receptor activation [16].
• Intrathecal MK 801 (an NMDA receptor antagonist), 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX; a non-NMDA receptor antagonist), or GM1 ganglioside (an intracellular PKC inhibitor) treatment was given to examine the effects of these agents on the development and expression of thermal hyperalgesia in morphine-tolerant rats [17].

Biological context of Grin1

• Here we report the cloning and characterization of the final member of the NMDAR family, NR3B, which shares high sequence homology with NR3A [1].
• When studied 28 d after the last evoked seizure, we found that kindling induced a 2.8-fold increase in the number of binding sites for the competitive NMDA receptor antagonist 3-[(+/-)-2-(carboxypiperazine-4-yl)][1,2-3H-]propyl-1-phosphonic acid (3H-CPP) [18].
• Gonadotropin-releasing hormone and NMDA receptor gene expression and colocalization change during puberty in female rats [3].
• NMDA receptors are assembled from several subunits (NMDAR1, NMDAR2A-D) encoded by five genes; alternative splicing gives rise to eight isoforms of subunit NMDAR1 [19].
• Neuronal plasticity associated with learning, memory and development is controlled, in part, by NMDA receptors, which are complexes consisting of the subunit NMDAR1 (NR1) and one or more NMDAR2 subunits (NR2A-NR2D) [20].

Anatomical context of Grin1

• These data reveal that NMDAR subunit composition in the visual cortex is remarkably dynamic and bidirectionally regulated by sensory experience [21].
• The differential expression of 16 NMDA and non-NMDA receptor subunits in the rat spinal cord and in periaqueductal gray [22].
• EM examination revealed dense staining in dendrites and postsynaptic densities in cerebral cortex and hippocampus, similar to those seen with antibody to NR1 [20].
• NMDA receptor subunit mRNA expression by projection neurons and interneurons in rat striatum [19].
• Expression of AMPA, kainate, and NMDA receptor subunits in cochlear and vestibular ganglia [23].

Associations of Grin1 with chemical compounds

• Excitatory glycine receptors containing the NR3 family of NMDA receptor subunits [1].
• Moreover, NR1/NR3A or -3B receptors form relatively Ca2+-impermeable cation channels that are resistant to Mg2+, MK-801, memantine and competitive antagonists [1].
• Each cysteine residue in the NMDAR1 (NR1) subunit and each conserved NMDAR2 (NR2) cysteine residue in a prototypical subunit (NR2B) was tested for its role in redox modulation [24].
• Thus, these striatal cell populations express different NMDAR-subunit mRNA phenotypes and therefore are likely to display NMDA channels with distinct pharmacological and physiological properties [19].
• Fourteen glutamate receptor subunits were studied: GluR1-4 (including flip and flop variants), GluR5-7, KA1&2, NR1, and NR2A-D [23].

Physical interactions of Grin1

• Since chi-1 did not alter the currents generated by non-NMDA subunits, this suggests that chi-1 may specifically interact with NMDA receptor subunits [25].
• Apo-calmodulin binds with its C-terminal domain to the N-methyl-D-aspartate receptor NR1 C0 region [26].
• The results suggest that morphine tolerance affects NMDA receptor binding activity and increases nNOS expression in the rat spinal cord [27].
• Both alphaCaMKII and PSD-95 have been shown previously to bind NR2 subunits of the NMDA receptor complex [28].
• We compared, for a number of ligands to the two receptors, the displacement of [3H]strychnine binding to the glycine-gated chloride channel of spinal cord and brainstem synaptic membranes to the displacement of [3H]glycine binding to the NMDA receptor complex of hippocampal and cortex synaptic membranes [29].

Enzymatic interactions of Grin1

• We now demonstrate that PKA and various PKC isoforms phosphorylate the NMDA receptor in vitro [30].

Co-localisations of Grin1

• BDNF was preferentially colocalized with glutamatergic markers VGLUT1 and NR1 ( approximately 30% each) [31].
• The majority of NMDA receptor clusters were colocalized with the postsynaptic density proteins PSD-95, PSD-93, and SAP 102 [32].
• However, after ischemia-induced neuronal death in these regions, double immunohistochemical labeling revealed that NR2B subunits colocalized with the astrocyte marker glial fibrillary acid protein and with NR1 subunits that are required for functional NMDA receptors [33].
• Calretinin co-localizes with the NMDA receptor subunit NR1 in cholinergic amacrine cells of the rat retina [34].

Regulatory relationships of Grin1

• Brain-derived neurotrophic factor induces NMDA receptor subunit one phosphorylation via ERK and PKC in the rat spinal cord [35].
• Brain-derived neurotrophic factor and basic fibroblast growth factor downregulate NMDA receptor function in cerebellar granule cells [2].
• NR2C and NR3 were expressed at levels which were approximately 15% of those of NR1 [36].
• We conclude that both age and IGF-1 regulate the expression of NMDA receptor subtypes and suggest that age-related changes in NMDA receptor heterogeneity may result in functional changes in the receptor that have relevance for aging [37].
• Thus, PKC regulates NMDAR channel gating and trafficking in recombinant systems and in neurons, mechanisms that may be relevant to synaptic plasticity [38].

Other interactions of Grin1

• In the cerebellum, in contrast to staining with NR1 antibody, Purkinje cell staining with NR2A/B antibody was low, indicating that these neurons may lack functional NMDA receptors [20].
• For the periaqueductal gray, prominent mRNAs were GluR-A, -B, and NR1 [22].
• The percentage of GnRH neurons that double-labeled with NMDA-R1 was 2% in prepubertal rats and 3% in pubertal rats; this increased to 19% in postpubertal rats [3].
• 4. Patches from these cells also contained 'low-conductance' NMDAR channels, with features characteristic of NR2D subunit-containing receptors [39].
• TrkB was also relatively highly colocalized with VGLUT1 and NR1 ( approximately 20% each) but was additionally highly colocalized with GABAergic markers GAD-65 ( approximately 20%) and gamma2 ( approximately 30%) [31].

Analytical, diagnostic and therapeutic context of Grin1

• We studied the expression of NMDA receptor subunits in neurochemically identified striatal neurons of adult rats by in situ hybridization histochemistry using a double-labeling technique [19].
• Sodium deoxycholate at pH 9.0 solubilized about 35% of the receptor, which was intact based on co-immunoprecipitation of NR1 and NR2 subunits and chemical cross-linking of the solubilized receptor [40].
• With the goal to determine quantitatively the subunit composition of cortical NMDA receptors, we used the monoclonal antibody to NR1 and polyclonal antibodies against the NR2A and NR2B subunits to perform immunoprecipitations of receptor subunits from solubilized adult rat cortical membranes [41].
• 3. Single channel measurements in outside-out patches combined with RT-PCR on the same cell showed that NMDA-R channels from these neurones had main single channel conductance levels of 42 pS in 2 mM Ca2+ and 49 pS in 1 mM Ca2+ [42].
• In the present study we investigated the modulation of hypothalamic NMDA receptor-mediated currents by cyclic AMP-dependent protein kinase (PKA) using the two-electrode voltage-clamp technique in XENOPUS: oocytes injected with rat hypothalamic mRNA [43].

References