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Gene Review

GRIA2  -  glutamate receptor, ionotropic, AMPA 2

Homo sapiens

Synonyms: AMPA-selective glutamate receptor 2, GLUR2, GLURB, GluA2, GluR-2, ...
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Disease relevance of GRIA2


Psychiatry related information on GRIA2


High impact information on GRIA2

  • Using the GluR2 AMPA-sensitive glutamate receptor, we show here that the ligand-binding cores form dimers and that stabilization of the intradimer interface by either mutations or allosteric modulators reduces desensitization [11].
  • Thus, the GluR-B editing enzyme may contain the adenosine deaminase, or a similar activity, and an RNA recognition subunit that specifically targets the enzyme to the editing site [12].
  • Here we show that the GluR-B pre-mRNA is efficiently and accurately edited in vitro, and that base-pair interactions between the editing site and a sequence in the downstream intron are required for substrate recognition [12].
  • The steady-state current-voltage (I-V) relations of glutamate- and kainate-induced currents through homomeric channels fell into two classes: channels composed of either the GluR-A, -C, and -D subunits showed doubly rectifying I-V curves, and channels composed of the GluR-B subunits displayed simple outward rectification [13].
  • The properties of heteromeric wild-type and mutant GluRs revealed that the dominance of GluR-B is due to the arginine residue in the TM2 region [13].

Biological context of GRIA2


Anatomical context of GRIA2


Associations of GRIA2 with chemical compounds

  • Uniquely, the loop 1 (L1) regions between hydrophobic domain 1 and hydrophobic domain 2 of the hagfish putative GRIA2 and all the teleost GRIA1 subunits were much longer than those of the remaining known ionotropic glutamate receptor subunits [21].
  • However, in rhesus monkeys chronically treated with antipsychotic drugs, clozapine treatment significantly decreased GRIA1 and increased GRIA3 mRNA expression, while both clozapine and haloperidol increased the expression of GRIA2 subunit mRNA [22].
  • Isoforms DRADA2c and -2d, which have a distinctive truncated shorter C-terminal structure, displayed weak adenosine-to-inosine conversion activity but no editing activity tested at three known sites of GluR-B RNA [23].
  • However, correcting for changes in neuron densities showed that hippocampal sclerosis patients had increased AMPA and NMDA mRNA levels per neuron compared with autopsies, and in the CA2 resistant sector GluR2 mRNA levels were numerically greater than autopsies and mass lesion cases [24].
  • 5-Fluorowillardiine (19) has higher affinity than AMPA for both homomeric hGluR1 and hGluR2 and compared to AMPA displays greater selectivity for AMPA receptor subtypes over the kainate receptor, hGluR5 [25].

Physical interactions of GRIA2


Enzymatic interactions of GRIA2

  • Editing of the human GluR-B transcript is catalyzed by the enzyme ADAR2 at the Q/R and R/G sites [26].
  • Pretreatment with WAY-100635 counteracted the NBQX effects and restored the initial learning-specific increase in Ca2+/calmodulin-dependent protein kinase II (CaMKII) function and the later increase in GluR2/3 and phosphorylated GluR1 surface expression [29].

Co-localisations of GRIA2

  • Immunostaining of cultured hippocampal neurons demonstrates that the Ser880-phosphorylated GluR2 subunits are enriched and colocalized with PICK1 in the dendrites, with very little staining observed at excitatory synapses [30].

Regulatory relationships of GRIA2

  • These results suggest that Q/R site of GluRs editing is regulated in a regional, and hence presumably cell-specific, manner and that the GluR2 Q/R site editing is critically regulated by ADAR2 in human brain [31].
  • The NMDA-induced GluR2 internalization was also observed in the absence of extracellular Na+ ions, suggesting that membrane depolarization is not a prerequisite for this effect [32].
  • NMDA-induced GluR2 endocytosis was completely inhibited by pharmacological block of NR2B-containing NMDARs [32].
  • The L-glutamate EC50 was 10.2 microM when wild-type GluR-A was coexpressed with GluR-B (GluR-A/B) and 38.9 microM when GluR-A445Q/B449Q receptors were tested [33].
  • These results implicate GluR2-lacking AMPA receptors in the ischemia-induced rise in free Zn(2+) and death of CA1 neurons, although a direct action at the time of the rise in Zn(2+) is unproven [34].

Other interactions of GRIA2

  • As originally reported for rat RED1, the DRADA2a and -2b isoforms edit GluR-B RNA efficiently at the so-called Q/R site, whereas DRADA1 barely edits this site [23].
  • Furthermore, GluR2/3 immunoreactivity had principally a somatic distribution whereas GluR5/6/7 labeling was predominately found in the perikarya and/or particular dendritic domains [35].
  • The GluR2 flip G variant showed the slowest desensitization (10.8 ms), GluR4 flip the fastest (1.6 ms) [36].
  • Interestingly, PKC activation in neurons increases the Ser880 phosphorylation of GluR2 subunits and recruits PICK1 to excitatory synapses [30].
  • Another case of RNA editing alters an arginine (R) to a glycine (G) codon at a position termed the "R/G" site of AMPA subunits GluR-B, C, and D. Double-stranded RNA-specific adenosine deaminases (DRADA) have been implicated as agents involved in the editing [37].

Analytical, diagnostic and therapeutic context of GRIA2

  • Furthermore, both the expression level and the proportion of GluR2 mRNA in motoneurons were the lowest among all neuronal subsets examined, whereas those in motoneurons of ALS did not differ from the control group, implying that selective reduction of the GluR2 subunit cannot be a mechanism of AMPA receptor-mediated neurotoxicity in ALS [38].
  • We used patch-clamp techniques with ultrafast solution exchange to examine the kinetics of recombinant human homomeric GluR2 flop channels transiently expressed in HEK293 cells [edited at the R/G site and Q/R/N site (GR), and unedited (RN) and edited (GN) at the R/G site both with asparagine (N) at the Q/R/N site] [17].
  • New potential regulators of uterine leiomyomata from DNA arrays: the ionotropic glutamate receptor GluR2 [3].
  • We assessed GluR2 protein expression in the BLA by immunocytochemistry with a GluR2 subunit-specific antiserum at the light and electron microscopic level; for comparison, a parallel examination was carried out in the hippocampus [39].
  • Immunohistochemical and double immunofluorescence results showed that the GluR2/3 were mainly expressed and co-localized with OX-42-positive microglia/macrophages and the glial fibrillary acidic protein (GFAP)-positive astrocytes [40].


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  3. New potential regulators of uterine leiomyomata from DNA arrays: the ionotropic glutamate receptor GluR2. Tsibris, J.C., Maas, S., Segars, J.H., Nicosia, S.V., Enkemann, S.A., O'Brien, W.F., Spellacy, W.N. Biochem. Biophys. Res. Commun. (2003) [Pubmed]
  4. Hypothermia rescues hippocampal CA1 neurons and attenuates down-regulation of the AMPA receptor GluR2 subunit after forebrain ischemia. Colbourne, F., Grooms, S.Y., Zukin, R.S., Buchan, A.M., Bennett, M.V. Proc. Natl. Acad. Sci. U.S.A. (2003) [Pubmed]
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  12. Editing of glutamate receptor subunit B pre-mRNA in vitro by site-specific deamination of adenosine. Yang, J.H., Sklar, P., Axel, R., Maniatis, T. Nature (1995) [Pubmed]
  13. Structural determinants of ion flow through recombinant glutamate receptor channels. Verdoorn, T.A., Burnashev, N., Monyer, H., Seeburg, P.H., Sakmann, B. Science (1991) [Pubmed]
  14. Molecular cloning, chromosomal mapping, and functional expression of human brain glutamate receptors. Sun, W., Ferrer-Montiel, A.V., Schinder, A.F., McPherson, J.P., Evans, G.A., Montal, M. Proc. Natl. Acad. Sci. U.S.A. (1992) [Pubmed]
  15. RNA editing (R/G site) and flip-flop splicing of the AMPA receptor subunit GluR2 in nervous tissue of epilepsy patients. Vollmar, W., Gloger, J., Berger, E., Kortenbruck, G., Köhling, R., Speckmann, E.J., Musshoff, U. Neurobiol. Dis. (2004) [Pubmed]
  16. Phosphorylation of serine-880 in GluR2 by protein kinase C prevents its C terminus from binding with glutamate receptor-interacting protein. Matsuda, S., Mikawa, S., Hirai, H. J. Neurochem. (1999) [Pubmed]
  17. Control of kinetic properties of GluR2 flop AMPA-type channels: impact of R/G nuclear editing. Krampfl, K., Schlesinger, F., Zörner, A., Kappler, M., Dengler, R., Bufler, J. Eur. J. Neurosci. (2002) [Pubmed]
  18. Calcium-permeable alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors: a molecular determinant of selective vulnerability in amyotrophic lateral sclerosis. Williams, T.L., Day, N.C., Ince, P.G., Kamboj, R.K., Shaw, P.J. Ann. Neurol. (1997) [Pubmed]
  19. RNA editing at the Q/R site for the glutamate receptor subunits GLUR2, GLUR5, and GLUR6 in hippocampus and temporal cortex from epileptic patients. Kortenbruck, G., Berger, E., Speckmann, E.J., Musshoff, U. Neurobiol. Dis. (2001) [Pubmed]
  20. Molecular cloning and differential expression patterns of avian glutamate receptor mRNAs. Ottiger, H.P., Gerfin-Moser, A., Del Principe, F., Dutly, F., Streit, P. J. Neurochem. (1995) [Pubmed]
  21. Identifications, classification, and evolution of the vertebrate alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor subunit genes. Chen, Y.C., Kung, S.S., Chen, B.Y., Hung, C.C., Chen, C.C., Wang, T.Y., Wu, Y.M., Lin, W.H., Tzeng, C.S., Chow, W.Y. J. Mol. Evol. (2001) [Pubmed]
  22. AMPA receptor subunit and splice variant expression in the DLPFC of schizophrenic subjects and rhesus monkeys chronically administered antipsychotic drugs. O'connor, J.A., Muly, E.C., Arnold, S.E., Hemby, S.E. Schizophr. Res. (2007) [Pubmed]
  23. Editing of glutamate receptor B subunit ion channel RNAs by four alternatively spliced DRADA2 double-stranded RNA adenosine deaminases. Lai, F., Chen, C.X., Carter, K.C., Nishikura, K. Mol. Cell. Biol. (1997) [Pubmed]
  24. Human hippocampal AMPA and NMDA mRNA levels in temporal lobe epilepsy patients. Mathern, G.W., Pretorius, J.K., Kornblum, H.I., Mendoza, D., Lozada, A., Leite, J.P., Chimelli, L.M., Fried, I., Sakamoto, A.C., Assirati, J.A., Lévesque, M.F., Adelson, P.D., Peacock, W.J. Brain (1997) [Pubmed]
  25. Synthesis of willardiine and 6-azawillardiine analogs: pharmacological characterization on cloned homomeric human AMPA and kainate receptor subtypes. Jane, D.E., Hoo, K., Kamboj, R., Deverill, M., Bleakman, D., Mandelzys, A. J. Med. Chem. (1997) [Pubmed]
  26. Adenosine to inosine editing by ADAR2 requires formation of a ternary complex on the GluR-B R/G site. Jaikaran, D.C., Collins, C.H., MacMillan, A.M. J. Biol. Chem. (2002) [Pubmed]
  27. Heteromeric AMPA receptors assemble with a preferred subunit stoichiometry and spatial arrangement. Mansour, M., Nagarajan, N., Nehring, R.B., Clements, J.D., Rosenmund, C. Neuron (2001) [Pubmed]
  28. Synaptic transmission: two players team up for a new tune. Jahn, R. Curr. Biol. (1998) [Pubmed]
  29. Opposing effects of AMPA and 5-HT1A receptor blockade on passive avoidance and object recognition performance: correlation with AMPA receptor subunit expression in rat hippocampus. Schiapparelli, L., Simón, A.M., Del Río, J., Frechilla, D. Neuropharmacology (2006) [Pubmed]
  30. Phosphorylation of the AMPA receptor subunit GluR2 differentially regulates its interaction with PDZ domain-containing proteins. Chung, H.J., Xia, J., Scannevin, R.H., Zhang, X., Huganir, R.L. J. Neurosci. (2000) [Pubmed]
  31. Low editing efficiency of GluR2 mRNA is associated with a low relative abundance of ADAR2 mRNA in white matter of normal human brain. Kawahara, Y., Ito, K., Sun, H., Kanazawa, I., Kwak, S. Eur. J. Neurosci. (2003) [Pubmed]
  32. Subunit dependencies of N-methyl-D-aspartate (NMDA) receptor-induced alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor internalization. Tigaret, C.M., Thalhammer, A., Rast, G.F., Specht, C.G., Auberson, Y.P., Stewart, M.G., Schoepfer, R. Mol. Pharmacol. (2006) [Pubmed]
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  34. Blockade of calcium-permeable AMPA receptors protects hippocampal neurons against global ischemia-induced death. Noh, K.M., Yokota, H., Mashiko, T., Castillo, P.E., Zukin, R.S., Bennett, M.V. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
  35. Quantitative localization of AMPA/kainate and kainate glutamate receptor subunit immunoreactivity in neurochemically identified subpopulations of neurons in the prefrontal cortex of the macaque monkey. Vickers, J.C., Huntley, G.W., Edwards, A.M., Moran, T., Rogers, S.W., Heinemann, S.F., Morrison, J.H. J. Neurosci. (1993) [Pubmed]
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  37. Dramatic increase of the RNA editing for glutamate receptor subunits during terminal differentiation of clonal human neurons. Lai, F., Chen, C.X., Lee, V.M., Nishikura, K. J. Neurochem. (1997) [Pubmed]
  38. Human spinal motoneurons express low relative abundance of GluR2 mRNA: an implication for excitotoxicity in ALS. Kawahara, Y., Kwak, S., Sun, H., Ito, K., Hashida, H., Aizawa, H., Jeong, S.Y., Kanazawa, I. J. Neurochem. (2003) [Pubmed]
  39. Evidence for low GluR2 AMPA receptor subunit expression at synapses in the rat basolateral amygdala. Gryder, D.S., Castaneda, D.C., Rogawski, M.A. J. Neurochem. (2005) [Pubmed]
  40. Expression of N-methyl-D-aspartate (NMDA) and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) GluR2/3 receptors in the developing rat pineal gland. Kaur, C., Sivakumar, V., Ling, E.A. J. Pineal Res. (2005) [Pubmed]
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