G2Cdb::Gene report

Gene id
Gene symbol
Homo sapiens
glutamate receptor, ionotrophic, AMPA 3
G00000059 (Mus musculus)

Databases (8)

Curated Gene
OTTHUMG00000022685 (Vega human gene)
ENSG00000125675 (Ensembl human gene)
2892 (Entrez Gene)
254 (G2Cdb plasticity & disease)
GRIA3 (GeneCards)
305915 (OMIM)
Marker Symbol
HGNC:4573 (HGNC)
Protein Sequence
P42263 (UniProt)

Synonyms (2)

  • MRX94

Literature (47)

Pubmed - other

  • A population-based association study of candidate genes for depression and sleep disturbance.

    Utge S, Soronen P, Partonen T, Loukola A, Kronholm E, Pirkola S, Nyman E, Porkka-Heiskanen T and Paunio T

    Public Health Genomics Unit, National Institute for Health and Welfare, Helsinki, Finland.

    The clinical manifestation of depression comprises a variety of symptoms, including early morning awakenings and fatigue, features also indicating disturbed sleep. The presence or absence of these symptoms may reflect differences in neurobiological processes leading to prolonged depression. Several neurobiological mechanisms have been indicated in the induction of depression, including disturbances in serotonergic and glutamatergic neurotransmission and in the action of the hypothalamic-pituitary-adrenal (HPA) axis. The same transmitters have also been linked to sleep regulation. We hypothesized that depression without simultaneous symptoms of disturbed sleep would partly have a different genetic background than depression with symptoms of disturbed sleep. We tested this hypothesis using a systematic population-based association study of 14 candidate genes related to depression and disturbed sleep. Association of genetic variants with either depression alone, depression with early morning awakenings, or depression with fatigue was investigated using permutation-based allelic association analysis of a sample of 1,654 adults recruited from Finland's population-based program. The major findings were associations of TPH2 (rs12229394) with depression accompanied by fatigue in women and CREB1 (rs11904814) with depression alone in men. We also found suggestive associations in women for GAD1, GRIA3, and BDNF with depression accompanied by fatigue, and for CRHR1 with depression accompanied by early morning awakenings. The results indicate sex-dependent and symptom-specific differences in the genetic background of depression. These differences may partially explain the broad spectrum of depressive symptoms, and their systematic monitoring could potentially be used for diagnostic purposes.

    American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics 2010;153B;2;468-476

  • Glutamatergic (N-methyl-D-aspartate receptor) hypofrontality in schizophrenia: too little juice or a miswired brain?

    Marek GJ, Behl B, Bespalov AY, Gross G, Lee Y and Schoemaker H

    Neuroscience Development, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, Illinois [corrected] 60064-6075, USA. gerard.marek@abbott.com

    Dopamine D2 receptor blockade has been an obligate mechanism of action present in all medications that effectively treat positive symptoms of schizophrenia (e.g., delusions and hallucinations) and have been approved by regulatory agencies since the 1950s. Blockade of 5-hydroxytryptamine(2A) receptors plays a contributory role in the actions of the second generation of antipsychotic drugs, the so-called atypical antipsychotics. Nevertheless, substantial unmet medical needs remain for the treatment of negative symptoms and cognitive dysfunction. Recognition that dissociative anesthetics block the N-methyl-D-aspartate (NMDA) receptor channel has inspired a search for glutamatergic therapeutic mechanisms because ketamine and phencyclidine are known to induce psychotic-like symptoms in healthy volunteers and exacerbate the symptoms of patients with schizophrenia. Current pathophysiological theories of schizophrenia emphasize that hypofunction of NMDA receptors at critical sites in local circuits modulate the function of a given brain region or control projections from one region to another (e.g., hippocampal-cortical or thalamocortical projections). The demonstration that a metabotropic glutamate 2/3 (mGlu2/3) receptor agonist prodrug decreased both positive and negative symptoms of schizophrenia raised hopes that glutamatergic mechanisms may provide therapeutic advantages. In addition to discussing the activation of mGlu2 receptors with mGlu2/3 receptor agonists or mGlu2 receptor positive allosteric modulators (PAMs), we discuss other methods that may potentially modulate circuits with hypofunctional NMDA receptors such as glycine transporter inhibitors and mGlu5 receptor PAMs. The hope is that by modulating glutamatergic neurotransmission, the dysfunctional circuitry of the schizophrenic brain (both local circuits and long-loop pathways) will be improved.

    Molecular pharmacology 2010;77;3;317-26

  • Identification of new putative susceptibility genes for several psychiatric disorders by association analysis of regulatory and non-synonymous SNPs of 306 genes involved in neurotransmission and neurodevelopment.

    Gratacòs M, Costas J, de Cid R, Bayés M, González JR, Baca-García E, de Diego Y, Fernández-Aranda F, Fernández-Piqueras J, Guitart M, Martín-Santos R, Martorell L, Menchón JM, Roca M, Sáiz-Ruiz J, Sanjuán J, Torrens M, Urretavizcaya M, Valero J, Vilella E, Estivill X, Carracedo A and Psychiatric Genetics Network Group

    CIBER en Epidemiología y Salud Pública (CIBERESP), Instituto de Salud Carlos III, Madrid, Spain.

    A fundamental difficulty in human genetics research is the identification of the spectrum of genetic variants that contribute to the susceptibility to common/complex disorders. We tested here the hypothesis that functional genetic variants may confer susceptibility to several related common disorders. We analyzed five main psychiatric diagnostic categories (substance-abuse, anxiety, eating, psychotic, and mood disorders) and two different control groups, representing a total of 3,214 samples, for 748 promoter and non-synonymous single nucleotide polymorphisms (SNPs) at 306 genes involved in neurotransmission and/or neurodevelopment. We identified strong associations to individual disorders, such as growth hormone releasing hormone (GHRH) with anxiety disorders, prolactin regulatory element (PREB) with eating disorders, ionotropic kainate glutamate receptor 5 (GRIK5) with bipolar disorder and several SNPs associated to several disorders, that may represent individual and related disease susceptibility factors. Remarkably, a functional SNP, rs945032, located in the promoter region of the bradykinin receptor B2 gene (BDKRB2) was associated to three disorders (panic disorder, substance abuse, and bipolar disorder), and two additional BDKRB2 SNPs to obsessive-compulsive disorder and major depression, providing evidence for common variants of susceptibility to several related psychiatric disorders. The association of BDKRB2 (odd ratios between 1.65 and 3.06) to several psychiatric disorders supports the view that a common genetic variant could confer susceptibility to clinically related phenotypes, and defines a new functional hint in the pathophysiology of psychiatric diseases.

    American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics 2009;150B;6;808-16

  • Recurrent rearrangements in synaptic and neurodevelopmental genes and shared biologic pathways in schizophrenia, autism, and mental retardation.

    Guilmatre A, Dubourg C, Mosca AL, Legallic S, Goldenberg A, Drouin-Garraud V, Layet V, Rosier A, Briault S, Bonnet-Brilhault F, Laumonnier F, Odent S, Le Vacon G, Joly-Helas G, David V, Bendavid C, Pinoit JM, Henry C, Impallomeni C, Germano E, Tortorella G, Di Rosa G, Barthelemy C, Andres C, Faivre L, Frébourg T, Saugier Veber P and Campion D

    Institut National de la Santé et de la Recherche Médicale, Unité 614, Institut Hospitalo-Universitaire de Recherche Biomédicale, 76000 Rouen, France.

    Context: Results of comparative genomic hybridization studies have suggested that rare copy number variations (CNVs) at numerous loci are involved in the cause of mental retardation, autism spectrum disorders, and schizophrenia.

    Objectives: To provide an estimate of the collective frequency of a set of recurrent or overlapping CNVs in 3 different groups of cases compared with healthy control subjects and to assess whether each CNV is present in more than 1 clinical category.

    Design: Case-control study.

    Setting: Academic research.

    Participants: We investigated 28 candidate loci previously identified by comparative genomic hybridization studies for gene dosage alteration in 247 cases with mental retardation, in 260 cases with autism spectrum disorders, in 236 cases with schizophrenia or schizoaffective disorder, and in 236 controls.

    Collective and individual frequencies of the analyzed CNVs in cases compared with controls.

    Results: Recurrent or overlapping CNVs were found in cases at 39.3% of the selected loci. The collective frequency of CNVs at these loci is significantly increased in cases with autism, in cases with schizophrenia, and in cases with mental retardation compared with controls (P < .001, P = .01, and P = .001, respectively, Fisher exact test). Individual significance (P = .02 without correction for multiple testing) was reached for the association between autism and a 350-kilobase deletion located at 22q11 and spanning the PRODH and DGCR6 genes.

    Conclusions: Weakly to moderately recurrent CNVs (transmitted or occurring de novo) seem to be causative or contributory factors for these diseases. Most of these CNVs (which contain genes involved in neurotransmission or in synapse formation and maintenance) are present in the 3 pathologic conditions (schizophrenia, autism, and mental retardation), supporting the existence of shared biologic pathways in these neurodevelopmental disorders.

    Archives of general psychiatry 2009;66;9;947-56

  • Pharmacogenetics of antipsychotic response in the CATIE trial: a candidate gene analysis.

    Need AC, Keefe RS, Ge D, Grossman I, Dickson S, McEvoy JP and Goldstein DB

    Center for Human Genome Variation, Institute for Genome Sciences & Policy, Duke University, Durham, NC 27708, USA.

    The Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) Phase 1 Schizophrenia trial compared the effectiveness of one typical and four atypical antipsychotic medications. Although trials such as CATIE present important opportunities for pharmacogenetics research, the very richness of the clinical data presents challenges for statistical interpretation, and in particular the risk that data mining will lead to false-positive discoveries. For this reason, it is both misleading and unhelpful to perpetuate the current practice of reporting association results for these trials one gene at a time, ignoring the fact that multiple gene-by-phenotype tests are being carried out on the same data set. On the other hand, suggestive associations in such trials may lead to new hypotheses that can be tested through both replication efforts and biological experimentation. The appropriate handling of these forms of data therefore requires dissemination of association statistics without undue emphasis on select findings. Here we attempt to illustrate this approach by presenting association statistics for 2769 polymorphisms in 118 candidate genes evaluated for 21 pharmacogenetic phenotypes. On current evidence it is impossible to know which of these associations may be real, although in total they form a valuable resource that is immediately available to the scientific community.

    Funded by: NIMH NIH HHS: N01 MH90001

    European journal of human genetics : EJHG 2009;17;7;946-57

  • Aberrant GRIA3 transcripts with multi-exon duplications in a family with X-linked mental retardation.

    Bonnet C, Leheup B, Béri M, Philippe C, Grégoire MJ and Jonveaux P

    Nancy Université, EA 4002, Laboratoire de Génétique, Centre Hospitalier Universitaire de Nancy, Vandoeuvre les Nancy, France.

    Investigation of chromosomal rearrangements in patients with mental retardation (MR) is particularly informative in the search for novel genes involved in MR. We report on a family with a genomic duplication at Xq25 identified by oligo array-CGH. Further characterization showed a partial tandem duplication of GRIA3 extending from exon 1 to exon 12. This duplication is present in two brothers with MR and on one allele in their sister with normal phenotype and completely skewed X-chromosome inactivation. The duplication is inherited from the mother, whose cognitive level is low and X-chromosome inactivation is random. This is the second family with partial duplication of GRIA3 associated with MR. GRIA3 expression studies in our case demonstrated a new mechanism for GRIA3 dysfunction with the presence of aberrant GRIA3 transcripts carrying multi-exon duplications leading to a frameshift. Our study gives additional support to the implication of GRIA3 in X-linked MR.

    American journal of medical genetics. Part A 2009;149A;6;1280-9

  • Genetic and clinical predictors of sexual dysfunction in citalopram-treated depressed patients.

    Perlis RH, Laje G, Smoller JW, Fava M, Rush AJ and McMahon FJ

    Department of Psychiatry, Massachusetts General Hospital, Boston, MA, USA. rperlis@partners.org

    Sexual dysfunction is a major contributor to treatment discontinuation and nonadherence among patients treated with selective serotonin reuptake inhibitors (SSRIs). The mechanisms by which depressive symptoms in general, as well as SSRI exposure in particular, may worsen sexual function are not known. We examined genetic polymorphisms, including those of the serotonin and glutamate systems, for association with erectile dysfunction, anorgasmia, and decreased libido during citalopram treatment. Clinical data were drawn from a nested case-control cohort derived from the STAR(*)D study, a multicenter, prospective, effectiveness trial in outpatients with nonpsychotic major depressive disorder (MDD). Self-reports of erectile dysfunction, decreased libido, or difficulty achieving orgasm based on the Patient-Rated Inventory of Side Effects were examined among Caucasian subjects (n=1473) for whom DNA and adverse effect measures were available, and who were treated openly with citalopram for up to 14 weeks. Of 1473 participants, 799 (54%) reported decreased libido; 525 (36%) reported difficulty achieving orgasm. Of 574 men, 211 (37%) reported erectile dysfunction. Using a set-based test for association, single nucleotide polymorphisms in glutamatergic genes were associated with decreased libido (GRIA3; GRIK2), difficulty achieving orgasm (GRIA1), and difficulty achieving erection (GRIN3A) (experiment-wide permuted p<0.05 for each). Evidence of association persisted after adjustment for baseline clinical and sociodemographic differences. Likewise, evidence of association was similar when the cohort was limited to those who did not report a given adverse event at the first post-baseline visit (ie, those whose adverse events were known to be treatment emergent). These hypothesis-generating analyses suggest the potential for glutamatergic treatment targets for sexual dysfunction during major depressive episodes.

    Funded by: NIMH NIH HHS: K23 MH067060

    Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 2009;34;7;1819-28

  • AMPA receptor trafficking and synaptic plasticity require SQSTM1/p62.

    Jiang J, Parameshwaran K, Seibenhener ML, Kang MG, Suppiramaniam V, Huganir RL, Diaz-Meco MT and Wooten MW

    Department of Biological Sciences and Program in Cellular and Molecular Biosciences, Auburn University, Auburn, Alabama 36849, USA.

    SQSTM1/p62 is a multidomain/scaffold for the atypical protein kinase Cs (aPKC). Phosphorylation of AMPA receptors by PKC has been shown to regulate their insertion in the postsynaptic membrane. Here, we directly tested whether p62 could interact with AMPA receptor subunits and influence their trafficking and phosphorylation. GluR1 receptor intracellular loop L2-3 and the ZZ-type zinc finger domain of p62 are essential for the interaction between these two proteins. In this context, both p62 and aPKC-mediated phosphorylation were necessary for surface delivery of the receptor. Our findings reveal that p62 is the first protein identified that interacts with a region of the GluR receptor other than the C-terminal tail. Furthermore, mice deficient in p62 displayed impaired hippocampal CA1 long-term potentiation (LTP), along with diminished surface expression of GluR1 and phosphorylation of S818. Lastly, we identify a conserved sequence (ISExSL) shared by all p62 interacting-aPKC substrates. These findings support a model where p62 interaction and aPKC phosphorylation act together to mediate AMPA receptor trafficking and long-term synaptic plasticity in the hippocampus.

    Funded by: Howard Hughes Medical Institute; NINDS NIH HHS: NS33661, R01 NS033661, R01 NS033661-09, R01 NS036715, R01 NS036715-08

    Hippocampus 2009;19;4;392-406

  • Synaptic AMPA receptor plasticity and behavior.

    Kessels HW and Malinow R

    Department of Neuroscience, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0634, USA. hkessels@ucsd.edu

    The ability to change behavior likely depends on the selective strengthening and weakening of brain synapses. The cellular models of synaptic plasticity, long-term potentiation (LTP) and depression (LTD) of synaptic strength, can be expressed by the synaptic insertion or removal of AMPA receptors (AMPARs), respectively. We here present an overview of studies that have used animal models to show that such AMPAR trafficking underlies several experience-driven phenomena-from neuronal circuit formation to the modification of behavior. We argue that monitoring and manipulating synaptic AMPAR trafficking represents an attractive means to study cognitive function and dysfunction in animal models.

    Funded by: NIA NIH HHS: AG032132, R01 AG032132; NIMH NIH HHS: MH049159, R01 MH049159, R37 MH049159

    Neuron 2009;61;3;340-50

  • Study on GRIA2, GRIA3 and GRIA4 genes highlights a positive association between schizophrenia and GRIA3 in female patients.

    Magri C, Gardella R, Valsecchi P, Barlati SD, Guizzetti L, Imperadori L, Bonvicini C, Tura GB, Gennarelli M, Sacchetti E and Barlati S

    Division of Biology and Genetics, Department of Biomedical Sciences and Biotechnology, Brescia University School of Medicine, Viale Europa, Brescia, Italy.

    Impairment of glutamatergic neurotransmission is one of the major hypotheses proposed to explain the neurobiology of schizophrenia. Therefore, the genes involved in the glutamate neurotransmitter system could be considered potential candidate genes for schizophrenia susceptibility. A systematic study on alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptor genes has been carried out and the results obtained from the analysis on GRIA2, GRIA3 and GRIA4 are reported. No evidence of association with schizophrenia was found for the GRIA2 and GRIA4 genes; strong evidence of association with schizophrenia was found for GRIA3. This X-linked gene showed a different behavior in the two genders; a positive association with schizophrenia was observed among females but not in males. Female carriers of rs1034428 A allele were found to have a 2.19-fold higher risk of developing schizophrenia compared to non-carriers and 3.28-fold higher risk for developing a non-paranoid phenotype. The analysis at the haplotype level showed that susceptibility to schizophrenia was associated with the specific haplotype rs989638-rs1034428-rs2227098 CAC (P = 0.0008). We conclude that, of the three AMPA genes analyzed here, only GRIA3 seems to be involved in the pathogenesis of schizophrenia, but only in females.

    American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics 2008;147B;6;745-53

  • Genetic markers within glutamate receptors associated with antidepressant treatment-emergent suicidal ideation.

    Menke A, Lucae S, Kloiber S, Horstmann S, Bettecken T, Uhr M, Ripke S, Ising M, Müller-Myhsok B, Holsboer F and Binder EB

    The American journal of psychiatry 2008;165;7;917-8

  • Motor protein-dependent transport of AMPA receptors into spines during long-term potentiation.

    Correia SS, Bassani S, Brown TC, Lisé MF, Backos DS, El-Husseini A, Passafaro M and Esteban JA

    Department of Pharmacology, University of Michigan Medical School, 1150 W. Medical Center Dr., Ann Arbor, Michigan 48109-0632, USA.

    The regulated trafficking of neurotransmitter receptors at synapses is critical for synaptic function and plasticity. However, the molecular machinery that controls active transport of receptors into synapses is largely unknown. We found that, in rat hippocampus, the insertion of AMPA receptors (AMPARs) into spines during synaptic plasticity requires a specific motor protein, which we identified as myosin Va. We found that myosin Va associates with AMPARs through its cargo binding domain. This interaction was enhanced by active, GTP-bound Rab11, which is also transported by the motor protein. Myosin Va mediated the CaMKII-triggered translocation of GluR1 receptors from the dendritic shaft into spines, but it was not required for constitutive GluR2 trafficking. Accordingly, myosin Va was specifically required for long-term potentiation, but not for basal synaptic transmission. In summary, we identified the specific motor protein and organelle acceptor that catalyze the directional transport of AMPARs into spines during activity-dependent synaptic plasticity.

    Funded by: NIMH NIH HHS: F31-MH070205, MH070417; Telethon: TCR07006

    Nature neuroscience 2008;11;4;457-66

  • Mutations in ionotropic AMPA receptor 3 alter channel properties and are associated with moderate cognitive impairment in humans.

    Wu Y, Arai AC, Rumbaugh G, Srivastava AK, Turner G, Hayashi T, Suzuki E, Jiang Y, Zhang L, Rodriguez J, Boyle J, Tarpey P, Raymond FL, Nevelsteen J, Froyen G, Stratton M, Futreal A, Gecz J, Stevenson R, Schwartz CE, Valle D, Huganir RL and Wang T

    Institute of Genetic Medicine and Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.

    Ionotropic alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors (iGluRs) mediate the majority of excitatory synaptic transmission in the CNS and are essential for the induction and maintenance of long-term potentiation and long-term depression, two cellular models of learning and memory. We identified a genomic deletion (0.4 Mb) involving the entire GRIA3 (encoding iGluR3) by using an X-array comparative genomic hybridization (CGH) and four missense variants (G833R, M706T, R631S, and R450Q) in functional domains of iGluR3 by sequencing 400 males with X-linked mental retardation (XLMR). Three variants were found in males with moderate MR and were absent in 500 control males. Expression studies in HEK293 cells showed that G833R resulted in a 78% reduction of iGluR3 due to protein misfolding. Whole-cell recording studies of iGluR3 homomers in HEK293 cells revealed that neither iGluR3-M706T (S2 domain) nor iGluR3-R631S (near channel core) had substantial channel function, whereas R450Q (S1 domain) was associated with accelerated receptor desensitization. When forming heteromeric receptors with iGluR2 in HEK293 cells, all four iGluR3 variants had altered desensitization kinetics. Our study provides the genetic and functional evidence that mutant iGluR3 with altered kinetic properties is associated with moderate cognitive impairment in humans.

    Funded by: NICHD NIH HHS: HD044789, HD24061, HD26202, K23 HD044789, P30 HD024061, R01 HD026202; NINDS NIH HHS: NS36715, NS41020, R01 NS036715, R01 NS041020

    Proceedings of the National Academy of Sciences of the United States of America 2007;104;46;18163-8

  • Electrophysiological properties of AMPA receptors are differentially modulated depending on the associated member of the TARP family.

    Kott S, Werner M, Körber C and Hollmann M

    Department of Biochemistry I, Receptor Biochemistry, Ruhr University Bochum, D-44780 Bochum, Germany.

    The family of AMPA receptors is encoded by four genes that are differentially spliced to result in the flip or flop versions of the four subunits GluR1 to GluR4. GluR2 is further modified at the so-called Q/R site by posttranscriptional RNA editing. Delivery of AMPA receptors to the plasma membrane and synaptic trafficking are controlled by transmembrane AMPA receptor regulatory proteins (TARPs). Additionally, TARPs influence essential electrophysiological properties of AMPA receptor channels such as desensitization and agonist efficacies. Here, we compare the influence of all known TARPs (gamma2, gamma3, gamma4, and gamma8) on agonist-induced currents of the four AMPA receptor subunits, including flip and flop splice variants and editing variants. We show that, although agonist-induced currents of all homomeric AMPA receptor subunits as well as all heteromeric combinations tested are significantly potentiated when coexpressed with members of the TARP family in Xenopus laevis oocytes, the extent of TARP-mediated increase in agonist-induced responses is highly dependent on both the AMPA receptor subunit and the coexpressed TARP. Moreover, we demonstrate that the splice variant of the AMPA receptor plays a key role in determining the modulation of electrophysiological properties by associated TARPs. We furthermore present evidence that individual TARP-AMPA receptor interactions control the degree of desensitization of AMPA receptors. Consequently, because of their subunit-specific impact on the electrophysiological properties, TARPs play a major role as modulatory subunits of AMPA receptors and thus contribute to the functional diversity of AMPA receptors encountered in the CNS.

    The Journal of neuroscience : the official journal of the Society for Neuroscience 2007;27;14;3780-9

  • TCR activation eliminates glutamate receptor GluR3 from the cell surface of normal human T cells, via an autocrine/paracrine granzyme B-mediated proteolytic cleavage.

    Ganor Y, Teichberg VI and Levite M

    Department of Neurobiology, Weizmann Institute of Science, Rehovot 76100, Israel.

    The majority of resting normal human T cells, like neuronal cells, express functional receptors for glutamate (the major excitatory neurotransmitter in the CNS) of the ionotropic alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-receptor subtype 3 (GluR3). Glutamate by itself ( approximately 10 nM) activates key T cell functions, including adhesion to fibronectin and laminin and chemotactic migration toward CXCL12/stromal cell-derived factor 1. In this study, we found by GluR3-specific immunostaining, flow cytometry, and Western blots that GluR3 cell surface expression decreases dramatically following TCR activation of human T cells. CXCR4, VLA-4, and VLA-6 also decrease substantially, whereas CD147 increases as expected, after TCR activation. Media of TCR-activated cells "eliminates" intact GluR3 (but not CXCR4 and VLA-6) from the cell surface of resting T cells, suggesting GluR3 cleavage by a soluble factor. We found that this factor is granzyme B (GB), a serine protease released by TCR-activated cells, because the extent of GluR3 elimination correlated with the active GB levels, and because three highly specific GB inhibitors blocked GluR3 down-regulation. Media of TCR-activated cells, presumably containing cleaved GluR3B peptide (GluR3 aa 372-388), inhibited the specific binding of anti-GluR3B mAb to synthetic GluR3B peptide. In parallel to losing intact GluR3, TCR-activated cells lost glutamate-induced adhesion to laminin. Taken together, our study shows that "classical immunological" TCR activation, via autocrine/paracrine GB, down-regulates substantially the expression of specific neurotransmitter receptors. Accordingly, glutamate T cell neuroimmune interactions are influenced by the T cell activation state, and glutamate, via AMPA-GluR3, may activate only resting, but not TCR-activated, T cells. Finally, the cleavage and release to the extracellular milieu of the GluR3B peptide may in principle increase its antigenicity, and thus the production, of anti-self GluR3B autoantibodies, which activate and kill neurons, found in patients with various types of epilepsy.

    Journal of immunology (Baltimore, Md. : 1950) 2007;178;2;683-92

  • Epilepsy-related ligand/receptor complex LGI1 and ADAM22 regulate synaptic transmission.

    Fukata Y, Adesnik H, Iwanaga T, Bredt DS, Nicoll RA and Fukata M

    Laboratory of Genomics and Proteomics, National Institute for Longevity Sciences, National Center for Geriatrics and Gerontology, Obu, Aichi 474-8522, Japan.

    Abnormally synchronized synaptic transmission in the brain causes epilepsy. Most inherited forms of epilepsy result from mutations in ion channels. However, one form of epilepsy, autosomal dominant partial epilepsy with auditory features (ADPEAF), is characterized by mutations in a secreted neuronal protein, LGI1. We show that ADAM22, a transmembrane protein that when mutated itself causes seizure, serves as a receptor for LGI1. LGI1 enhances AMPA receptor-mediated synaptic transmission in hippocampal slices. The mutated form of LGI1 fails to bind to ADAM22. ADAM22 is anchored to the postsynaptic density by cytoskeletal scaffolds containing stargazin. These studies in rat brain indicate possible avenues for understanding human epilepsy.

    Science (New York, N.Y.) 2006;313;5794;1792-5

  • Genomic annotation of 15,809 ESTs identified from pooled early gestation human eyes.

    Choy KW, Wang CC, Ogura A, Lau TK, Rogers MS, Ikeo K, Gojobori T, Lam DS and Pang CP

    Department of Ophthalmology, Chinese University of Hong Kong, Hong Kong.

    To complement cDNA libraries from the human eye at early gestation and to discover candidate genes associated with early ocular development, we used freshly dissected human eyeballs from week 9-14 of gestation to construct the early human fetal eye cDNA library. A total of 15,809 clones were isolated and sequenced from the unamplified and unnormalized library. We screened 11,246 good-quality ESTs, leading to the identification of 5,534 nonredundant clusters. Among them, 4,010 (72%) genes matched in the human protein database (Ensembl). The remaining 28% (1,524) corresponded to potentially novel or previously unidentified ESTs. We used BLASTX to compare our EST data with eight organisms and found common expression of a high portion of genes: Caenorhabditis briggsae (26%), Caenorhabditis elegans (27%), Anopheles gambiae (37%), Drosophila melanogaster (32%), Danio rerio (42%), Fugu rubripes (49%), Rattus norvegicusvalitus (52%), and Mus musculus (59%). Nevertheless, 48% (2,680 of 5,534) of the genes expressed in the early developing eye were not shared with current NEIBank human eye cDNA data. In addition, eight known retinal disease genes existed in our ESTs. Among them, six (COL11A1, BBS5, PDE6B, OAT, VMD2, and PGK1) were conserved among the genomes of other organisms, indicating that our annotated EST set provides not only a valuable resource for gene discovery and functional genomic analysis but also for phylogenetic analysis. Our foremost early gestation human eye cDNA library could provide detailed comparisons across species to identify physiological functions of genes and to elucidate evolutionary mechanisms.

    Physiological genomics 2006;25;1;9-15

  • Diversification of transcriptional modulation: large-scale identification and characterization of putative alternative promoters of human genes.

    Kimura K, Wakamatsu A, Suzuki Y, Ota T, Nishikawa T, Yamashita R, Yamamoto J, Sekine M, Tsuritani K, Wakaguri H, Ishii S, Sugiyama T, Saito K, Isono Y, Irie R, Kushida N, Yoneyama T, Otsuka R, Kanda K, Yokoi T, Kondo H, Wagatsuma M, Murakawa K, Ishida S, Ishibashi T, Takahashi-Fujii A, Tanase T, Nagai K, Kikuchi H, Nakai K, Isogai T and Sugano S

    Life Science Research Laboratory, Central Research Laboratory, Hitachi, Ltd., Kokubunji, Tokyo, 185-8601, Japan.

    By analyzing 1,780,295 5'-end sequences of human full-length cDNAs derived from 164 kinds of oligo-cap cDNA libraries, we identified 269,774 independent positions of transcriptional start sites (TSSs) for 14,628 human RefSeq genes. These TSSs were clustered into 30,964 clusters that were separated from each other by more than 500 bp and thus are very likely to constitute mutually distinct alternative promoters. To our surprise, at least 7674 (52%) human RefSeq genes were subject to regulation by putative alternative promoters (PAPs). On average, there were 3.1 PAPs per gene, with the composition of one CpG-island-containing promoter per 2.6 CpG-less promoters. In 17% of the PAP-containing loci, tissue-specific use of the PAPs was observed. The richest tissue sources of the tissue-specific PAPs were testis and brain. It was also intriguing that the PAP-containing promoters were enriched in the genes encoding signal transduction-related proteins and were rarer in the genes encoding extracellular proteins, possibly reflecting the varied functional requirement for and the restricted expression of those categories of genes, respectively. The patterns of the first exons were highly diverse as well. On average, there were 7.7 different splicing types of first exons per locus partly produced by the PAPs, suggesting that a wide variety of transcripts can be achieved by this mechanism. Our findings suggest that use of alternate promoters and consequent alternative use of first exons should play a pivotal role in generating the complexity required for the highly elaborated molecular systems in humans.

    Genome research 2006;16;1;55-65

  • PICK1 interacts with ABP/GRIP to regulate AMPA receptor trafficking.

    Lu W and Ziff EB

    Program in Neuroscience and Physiology, New York University School of Medicine, New York, New York 10016, USA.

    PICK1 and ABP/GRIP bind to the AMPA receptor (AMPAR) GluR2 subunit C terminus. Transfer of the receptor from ABP/GRIP to PICK1, facilitated by GluR2 S880 phosphorylation, may initiate receptor trafficking. Here we report protein interactions that regulate these steps. The PICK1 BAR domain interacts intermolecularly with the ABP/GRIP linker II region and intramolecularly with the PICK1 PDZ domain. Binding of PKCalpha or GluR2 to the PICK1 PDZ domain disrupts the intramolecular interaction and facilitates the PICK1 BAR domain association with ABP/GRIP. Interference with the PICK1-ABP/GRIP interaction impairs S880 phosphorylation of GluR2 by PKC and decreases the constitutive surface expression of GluR2, the NMDA-induced endocytosis of GluR2, and recycling of internalized GluR2. We suggest that the PICK1 interaction with ABP/GRIP is a critical step in controlling GluR2 trafficking.

    Funded by: NIMH NIH HHS: MH067229

    Neuron 2005;47;3;407-21

  • The DNA sequence of the human X chromosome.

    Ross MT, Grafham DV, Coffey AJ, Scherer S, McLay K, Muzny D, Platzer M, Howell GR, Burrows C, Bird CP, Frankish A, Lovell FL, Howe KL, Ashurst JL, Fulton RS, Sudbrak R, Wen G, Jones MC, Hurles ME, Andrews TD, Scott CE, Searle S, Ramser J, Whittaker A, Deadman R, Carter NP, Hunt SE, Chen R, Cree A, Gunaratne P, Havlak P, Hodgson A, Metzker ML, Richards S, Scott G, Steffen D, Sodergren E, Wheeler DA, Worley KC, Ainscough R, Ambrose KD, Ansari-Lari MA, Aradhya S, Ashwell RI, Babbage AK, Bagguley CL, Ballabio A, Banerjee R, Barker GE, Barlow KF, Barrett IP, Bates KN, Beare DM, Beasley H, Beasley O, Beck A, Bethel G, Blechschmidt K, Brady N, Bray-Allen S, Bridgeman AM, Brown AJ, Brown MJ, Bonnin D, Bruford EA, Buhay C, Burch P, Burford D, Burgess J, Burrill W, Burton J, Bye JM, Carder C, Carrel L, Chako J, Chapman JC, Chavez D, Chen E, Chen G, Chen Y, Chen Z, Chinault C, Ciccodicola A, Clark SY, Clarke G, Clee CM, Clegg S, Clerc-Blankenburg K, Clifford K, Cobley V, Cole CG, Conquer JS, Corby N, Connor RE, David R, Davies J, Davis C, Davis J, Delgado O, Deshazo D, Dhami P, Ding Y, Dinh H, Dodsworth S, Draper H, Dugan-Rocha S, Dunham A, Dunn M, Durbin KJ, Dutta I, Eades T, Ellwood M, Emery-Cohen A, Errington H, Evans KL, Faulkner L, Francis F, Frankland J, Fraser AE, Galgoczy P, Gilbert J, Gill R, Glöckner G, Gregory SG, Gribble S, Griffiths C, Grocock R, Gu Y, Gwilliam R, Hamilton C, Hart EA, Hawes A, Heath PD, Heitmann K, Hennig S, Hernandez J, Hinzmann B, Ho S, Hoffs M, Howden PJ, Huckle EJ, Hume J, Hunt PJ, Hunt AR, Isherwood J, Jacob L, Johnson D, Jones S, de Jong PJ, Joseph SS, Keenan S, Kelly S, Kershaw JK, Khan Z, Kioschis P, Klages S, Knights AJ, Kosiura A, Kovar-Smith C, Laird GK, Langford C, Lawlor S, Leversha M, Lewis L, Liu W, Lloyd C, Lloyd DM, Loulseged H, Loveland JE, Lovell JD, Lozado R, Lu J, Lyne R, Ma J, Maheshwari M, Matthews LH, McDowall J, McLaren S, McMurray A, Meidl P, Meitinger T, Milne S, Miner G, Mistry SL, Morgan M, Morris S, Müller I, Mullikin JC, Nguyen N, Nordsiek G, Nyakatura G, O'Dell CN, Okwuonu G, Palmer S, Pandian R, Parker D, Parrish J, Pasternak S, Patel D, Pearce AV, Pearson DM, Pelan SE, Perez L, Porter KM, Ramsey Y, Reichwald K, Rhodes S, Ridler KA, Schlessinger D, Schueler MG, Sehra HK, Shaw-Smith C, Shen H, Sheridan EM, Shownkeen R, Skuce CD, Smith ML, Sotheran EC, Steingruber HE, Steward CA, Storey R, Swann RM, Swarbreck D, Tabor PE, Taudien S, Taylor T, Teague B, Thomas K, Thorpe A, Timms K, Tracey A, Trevanion S, Tromans AC, d'Urso M, Verduzco D, Villasana D, Waldron L, Wall M, Wang Q, Warren J, Warry GL, Wei X, West A, Whitehead SL, Whiteley MN, Wilkinson JE, Willey DL, Williams G, Williams L, Williamson A, Williamson H, Wilming L, Woodmansey RL, Wray PW, Yen J, Zhang J, Zhou J, Zoghbi H, Zorilla S, Buck D, Reinhardt R, Poustka A, Rosenthal A, Lehrach H, Meindl A, Minx PJ, Hillier LW, Willard HF, Wilson RK, Waterston RH, Rice CM, Vaudin M, Coulson A, Nelson DL, Weinstock G, Sulston JE, Durbin R, Hubbard T, Gibbs RA, Beck S, Rogers J and Bentley DR

    The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, UK. mtr@sanger.ac.uk

    The human X chromosome has a unique biology that was shaped by its evolution as the sex chromosome shared by males and females. We have determined 99.3% of the euchromatic sequence of the X chromosome. Our analysis illustrates the autosomal origin of the mammalian sex chromosomes, the stepwise process that led to the progressive loss of recombination between X and Y, and the extent of subsequent degradation of the Y chromosome. LINE1 repeat elements cover one-third of the X chromosome, with a distribution that is consistent with their proposed role as way stations in the process of X-chromosome inactivation. We found 1,098 genes in the sequence, of which 99 encode proteins expressed in testis and in various tumour types. A disproportionately high number of mendelian diseases are documented for the X chromosome. Of this number, 168 have been explained by mutations in 113 X-linked genes, which in many cases were characterized with the aid of the DNA sequence.

    Nature 2005;434;7031;325-37

  • Metabotropic glutamate receptors are expressed in adult human glial progenitor cells.

    Luyt K, Varadi A, Halfpenny CA, Scolding NJ and Molnar E

    MRC Centre for Synaptic Plasticity, Department of Anatomy, University of Bristol, School of Medical Sciences, University Walk, Bristol BS8 1TD, UK.

    Glial precursor cells (GPCs) are present in the adult human central nervous system (CNS) and they can be isolated and maintained in culture for in vitro studies. This study analysed expression of mGluR3 and mGluR5 metabotropic glutamate receptor (mGluR) mRNAs in GPCs. A2B5 surface antigen positive GPCs were isolated using immunomagnetic selection from dissociated temporal lobe subcortical white matter cells. The separated GPCs were maintained in cultures and characterised by immunoreactivity for the differentiation markers A2B5 and human platelet-derived growth factor-alpha receptor (PDGFalphaR). Reverse transcription followed by multiplex PCR analysis showed that the GPCs expressed both mGluR3 and mGluR5a mRNAs. Double immunostaining for glial progenitor markers and mGluR5 proteins demonstrated that all A2B5 and PDGFalphaR-positive cells were also positive for mGluR5. The results indicate that GPCs present in the adult human CNS express mGluR3 and mGluR5a. These neurotransmitter receptors may be involved in the proliferation and differentiation of glial cells.

    Biochemical and biophysical research communications 2004;319;1;120-9

  • Differential preservation of AMPA receptor subunits in the hippocampi of Alzheimer's disease patients according to Braak stage.

    Carter TL, Rissman RA, Mishizen-Eberz AJ, Wolfe BB, Hamilton RL, Gandy S and Armstrong DM

    Laboratory of Neuronal Vulnerability and Aging, The Lankenau Institute for Medical Research, Jefferson Health System, Wynewood, PA 19096, USA. Troy.Carter@jefferson.edu

    The Alzheimer's disease (AD) brain, characterized pathologically by the presence of senile plaques and neurofibrillary tangles, contains regions that are differentially prone toward development of AD pathology. Within these "vulnerable" regions, specific cell populations appear to be selectively affected; the pyramidal cells of the hippocampal subiculum subfield constitute such a vulnerable region. This study investigated whether the AMPA receptor subunit content (GluR1, GluR2, GluR2/3) within "vulnerable" vs. "resistant" sectors of the hippocampus is quantitatively altered with increasing AD neuropathology, as determined by Braak staging. We hypothesize that the glutamate-mediated vulnerability is highly influenced by the repertoire of glutamate receptors expressed on hippocampal neurons. Our results indicate that AMPA receptor subunit proteins are relatively spared across all Braak stages in resistant subfields (CA2/CA3/Dentate Gyrus). However, within vulnerable sectors, i.e., subiculum, GluR2, and GluR2/3 protein levels decreased 63.77% and 60.60%, respectively, in association with Braak stages I-II and stages III-IV, respectively. In Braak stages V-VI, GluR2 and GluR2/3 protein levels were similar to those of Braak stages I-II. In contrast to GluR2 and GluR2/3, GluR1 protein levels were unchanged within vulnerable sectors throughout all stages of the disease. In interpreting these data, it may be relevant to consider that the GluR2 subunit impedes the flow of Ca(+2) through the AMPA receptor ion channel. Thus, we hypothesize that in resistant sectors, the presence of the GluR2 subunit may provide a neuroprotective role by limiting the flow of extracellular Ca(+2), whereas in vulnerable regions, the reduction of GluR2 may contribute to the vulnerability via a mechanism involving an increase in intracellular Ca(+2) and destabilization of intracellular Ca(+2) homeostasis.

    Funded by: NIA NIH HHS: AG08206, AG10491; NINDS NIH HHS: NS41017

    Experimental neurology 2004;187;2;299-309

  • AMPA receptor alterations precede mossy fiber sprouting in young children with temporal lobe epilepsy.

    Lynd-Balta E, Pilcher WH and Joseph SA

    Department of Neurosurgery, University of Rochester Medical Center, Rochester, NY 14642, USA.

    Following neurological injury early in life numerous events, including excitotoxicity, neural degeneration, gliosis, neosynaptogenesis, and circuitry reorganization, may alone or in concert contribute to hyperexcitability and recurrent seizures in temporal lobe epilepsy. Our studies provide new evidence regarding the temporal sequence of key elements of hippocampal reorganization, mossy fiber sprouting and glutamate receptor subunit up-regulation, in a subset of young temporal lobe epileptic patients. Without evidence of mossy fiber sprouting, the youngest age group (3-10 years old) of mesial temporal lobe epileptic patients demonstrated enhanced glutamate receptor subunit profiles, suggesting that the dendritic change precedes axonal sprouting. However, sclerotic hippocampal specimens from epileptic patients ages 12-15 years old had the characteristic features of glutamate receptor up-regulation and mossy fiber sprouting first identified in the adult, indicating that reconstructed circuits appear early in the course of the disease. Non-sclerotic hippocampal specimens from lesion associated temporal lobe epileptic patients of all age groups showed minimal cell loss, sparse staining of glutamate receptor subunits in the dentate gyrus, and little or no mossy fiber sprouting. These compelling findings suggest a progressive sequence of events in the reorganization of the dentate gyrus of sclerotic hippocampal specimens. We suggest that cell loss and up-regulation of glutamate receptor subunits appear early in temporal lobe epilepsy and contribute to the synaptic plasticity that may facilitate the subsequent sprouting of mossy fiber collaterals which compound an already precipitous state of decline. The combination of pre-synaptic and post-synaptic changes serves as a potential substrate for hyperexcitability.

    Neuroscience 2004;126;1;105-14

  • Protein phosphatase 2C binds selectively to and dephosphorylates metabotropic glutamate receptor 3.

    Flajolet M, Rakhilin S, Wang H, Starkova N, Nuangchamnong N, Nairn AC and Greengard P

    Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University, 1230 York Avenue, New York, NY 10021, USA.

    Cell surface receptor membrane localization is strongly dependent on protein-protein interactions often involving regulation by phosphorylation/dephosphorylation of the intracellular domains of membrane proteins. The present study was carried out to identify metabotropic glutamate receptor (mGluR) 3 regulatory binding proteins. Using the yeast two-hybrid technique, we found that the 50-aa C-terminal cytoplasmic tail of mGluR3 interacts specifically with protein phosphatase 2Calpha (PP2Calpha). This interaction was confirmed by GST pull-down and coimmunoprecipitation assays. mGluR3 interacts with PP2Calpha, beta, gamma, and delta isoforms; however, among the mGluR family only mGluR3 interacted with PP2C. The minimal interacting domain of mGluR3 comprised residues 836-855. Alignment between mGluR3 and mGluR2, a closely related group II receptor, indicated that this domain is not conserved between the two receptors. The mGluR3 cytoplasmic C-terminal tail contains one phosphorylation site for protein kinase A (Ser-845), but the phosphatase that dephosphorylates this site has not been previously identified. We find that PP2C, but not PP1, PP2A, or PP2B, dephosphorylates the mGluR3 cytoplasmic tail in vitro. The dephosphorylated form of the mGluR3 cytoplasmic tail, but not the equivalent region of mGluR2, inhibited PP2C assayed by using [32P]casein as a substrate. However, phosphorylation of the mGluR3 cytoplasmic tail at Ser-845 inhibits the interaction with PP2C. These results indicate distinct functions for mGluR2 and mGluR3 and suggest a dynamic regulation of mGluR3 by PP2C.

    Funded by: NIDA NIH HHS: DA10044, P01 DA010044; NIMH NIH HHS: MH40899, P01 MH040899

    Proceedings of the National Academy of Sciences of the United States of America 2003;100;26;16006-11

  • Glutamatergic plasticity by synaptic delivery of GluR-B(long)-containing AMPA receptors.

    Kolleker A, Zhu JJ, Schupp BJ, Qin Y, Mack V, Borchardt T, Köhr G, Malinow R, Seeburg PH and Osten P

    Max Planck Institute for Medical Research, Department of Molecular Neurobiology, Jahnstrasse 29, 69120, Heidelberg, Germany.

    Activity-driven delivery of AMPA receptors is proposed to mediate glutamatergic synaptic plasticity, both during development and learning. In hippocampal CA1 principal neurons, such trafficking is primarily mediated by the abundant GluR-A subunit. We now report a study of GluR-B(long), a C-terminal splice variant of the GluR-B subunit. GluR-B(long) synaptic delivery is regulated by two forms of activity. Spontaneous synaptic activity-driven GluR-B(long) transport maintains one-third of the steady-state AMPA receptor-mediated responses, while GluR-B(long) delivery following the induction of LTP is responsible for approximately 50% of the resulting potentiation at the hippocampal CA3 to CA1 synapses at the time of GluR-B(long) peak expression-the second postnatal week. Trafficking of GluR-B(long)-containing receptors thus mediates a GluR-A-independent form of glutamatergic synaptic plasticity in the juvenile hippocampus.

    Neuron 2003;40;6;1199-212

  • Human T cells express a functional ionotropic glutamate receptor GluR3, and glutamate by itself triggers integrin-mediated adhesion to laminin and fibronectin and chemotactic migration.

    Ganor Y, Besser M, Ben-Zakay N, Unger T and Levite M

    Weizmann Institute of Science, Rehovot, Israel. Sackler Faculty of Medicine, Tel-Aviv University, Ramat Aviv, Israel.

    T cells may encounter glutamate, the major excitatory neurotransmitter in the nervous system, when patrolling the brain and in glutamate-rich peripheral organs. Moreover, glutamate levels increase in the CNS in many pathological conditions in which T cells exert either beneficial or detrimental effects. We discovered that normal human T cells, human T leukemia cells, and mouse anti-myelin basic protein T cells express high levels of glutamate ion channel receptor (ionotropic) of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) subtype 3 (GluR3). The evidence for GluR3 on T cells includes GluR3-specific RT-PCR, Western blot, immunocytochemical staining and flow cytometry. Sequencing showed that the T cell-expressed GluR3 is identical with the brain GluR3. Glutamate (10 nM), in the absence of any additional molecule, triggered T cell function: integrin-mediated T cell adhesion to laminin and fibronectin, a function normally performed by activated T cells only. The effect of glutamate was mimicked by AMPA receptor-agonists and blocked specifically by the selective receptor-antagonists 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) and 6-nitro-7-sulfamoylbenzo[f]quinoxalin-2,3-dione (NBQX), and by relevant anti-integrin mAbs. Glutamate also increased the CXCR4-mediated T cell chemotactic migration toward the key chemokine CXCL12/stromal cell-derived factor-1. GluR3 expression on normal, cancer and autoimmune-associated T cells and the ability of glutamate to directly activate T cell function could be of substantial scientific and clinical importance to normal neuroimmune dialogues and to CNS diseases and injury, and especially to: 1) T cell transmigration to the CNS and patrolling in the brain, 2) T cell-mediated multiple sclerosis, and 3) autoimmune epilepsy, as neurotoxic anti-GluR3 Abs are found and suspected to cause/potentiate seizures and neuropathology in several types of human epilepsies. Thus far, GluR3 was found only on neurons and glia cells; our results reveal a novel peripheral source of this antigenic receptor.

    Journal of immunology (Baltimore, Md. : 1950) 2003;170;8;4362-72

  • Flip and flop splice variants of AMPA receptor subunits in the spinal cord of amyotrophic lateral sclerosis.

    Tomiyama M, Rodríguez-Puertas R, Cortés R, Pazos A, Palacios JM and Mengod G

    Department of Neurochemistry, Instituto de Investigaciones Biomédicas de Barcelona, Consejo Superior de Investigaciones Científicas (IIBB-CSIC, IDIBAPS), 08036 Barcelona, Spain.

    Excitotoxicity mediated by AMPA receptors has been suggested to be implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS). To investigate the relevance of AMPA receptors to motor neuron degeneration in ALS, we evaluated the expression of mRNAs coding for flip and flop splice variants of AMPA receptor subunits (GluR-A to GluR-D) in the cervical segment of the spinal cord from control individuals and patients with ALS using in situ hybridization histochemistry. Transcript mRNAs coding for flop variants were significantly decreased in the ventral horn of the spinal cord from patients with ALS, whereas the mRNAs for flip variants were preserved. These findings suggest that the relative abundance of flip variants vs. flop variants is increased in spinal motor neurons of ALS patients when compared to that of control individuals. Flip variants promote assemblies of slowly desensitizing AMPA receptors. These results imply that spinal motor neurons of ALS patients possess more slowly desensitizing AMPA receptors than those of control individuals. This expression change of AMPA receptors in ALS may account for vulnerability of motor neurons in this disease.

    Synapse (New York, N.Y.) 2002;45;4;245-9

  • Blockage of Ca(2+)-permeable AMPA receptors suppresses migration and induces apoptosis in human glioblastoma cells.

    Ishiuchi S, Tsuzuki K, Yoshida Y, Yamada N, Hagimura N, Okado H, Miwa A, Kurihara H, Nakazato Y, Tamura M, Sasaki T and Ozawa S

    Department of Neurosurgery, Gunma University School of Medicine, Maebashi, Gunma, Japan. ishogo@showa.gunma-u.ac.jp

    Glioblastoma multiforme is the most undifferentiated type of brain tumor, and its prognosis is extremely poor. Glioblastoma cells exhibit highly migratory and invasive behavior, which makes surgical intervention unsuccessful. Here, we showed that glioblastoma cells express Ca(2+)-permeable alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA)-type glutamate receptors assembled from the GluR1 and/or GluR4 subunits, and that their conversion to Ca(2+)-impermeable receptors by adenovirus-mediated transfer of the GluR2 cDNA inhibited cell locomotion and induced apoptosis. In contrast, overexpression of Ca(2+)-permeable AMPA receptors facilitated migration and proliferation of the tumor cells. These findings indicate that Ca(2+)-permeable AMPA receptors have crucial roles in growth of glioblastoma. Blockage of these Ca(2+)-permeable receptors may be a useful therapeutic strategy for the prevention of glioblastoma invasion.

    Nature medicine 2002;8;9;971-8

  • The PDZ proteins PICK1, GRIP, and syntenin bind multiple glutamate receptor subtypes. Analysis of PDZ binding motifs.

    Hirbec H, Perestenko O, Nishimune A, Meyer G, Nakanishi S, Henley JM and Dev KK

    Department of Anatomy, Medical Research Council Centre of Synaptic Plasticity, Medical School, University of Bristol, Bristol BS8 1TD, United Kingdom.

    Using sequence homology searches, yeast two-hybrid assays and glutathione S-transferase (GST)-pull-down approaches we have identified a series of glutamate receptor subunits that interact differentially with the PDZ proteins GRIP, PICK1, and syntenin. GST-pull-down experiments identified more interactions than detected by yeast two-hybrid assays. We report several receptor-protein interactions, strong ones include: (i) GRIP and syntenin with mGluR7a, mGluR4a, and mGluR6; (ii) PICK1 and GRIP with mGluR3; and (iii) syntenin with all forms of GluR1-4 and mGluR7b. We further characterized the novel mGluR7a-GRIP interaction found both in yeast two-hybrid and GST-pull-down assays and observed that mGluR7a localization overlapped with GRIP with in hippocampal neurons. The wide range of targets for PICK1, GRIP, and syntenin suggests they may represent a molecular mechanism that can concentrate and/or regulate a number of different receptors at a common site on a synapse. These data also suggest that the structural determinants involved in PDZ interactions are more complex than originally envisaged.

    Funded by: Medical Research Council: G9629038

    The Journal of biological chemistry 2002;277;18;15221-4

  • Interaction between GRIP and liprin-alpha/SYD2 is required for AMPA receptor targeting.

    Wyszynski M, Kim E, Dunah AW, Passafaro M, Valtschanoff JG, Serra-Pagès C, Streuli M, Weinberg RJ and Sheng M

    Department of Neurobiology and Howard Hughes Medical Institute, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.

    Interaction with the multi-PDZ protein GRIP is required for the synaptic targeting of AMPA receptors, but the underlying mechanism is unknown. We show that GRIP binds to the liprin-alpha/SYD2 family of proteins that interact with LAR receptor protein tyrosine phosphatases (LAR-RPTPs) and that are implicated in presynaptic development. In neurons, liprin-alpha and LAR-RPTP are enriched at synapses and coimmunoprecipitate with GRIP and AMPA receptors. Dominant-negative constructs that interfere with the GRIP-liprin interaction disrupt the surface expression and dendritic clustering of AMPA receptors in cultured neurons. Thus, by mediating the targeting of liprin/GRIP-associated proteins, liprin-alpha is important for postsynaptic as well as presynaptic maturation.

    Funded by: NCI NIH HHS: CA 55547; NINDS NIH HHS: NS35050

    Neuron 2002;34;1;39-52

  • [Linkage analysis and mutation detection of GRIA3 in Smith--Fineman--Myers syndrome].

    Liu QJ, Gong YQ, Chen BX, Guo CH, Li JX and Guo YS

    Department of Medical Genetics, Shandong University, School of Medicine, Jinan 250012, China.

    To determine the role of GRIA3 in the etiology of Smith--Fineman--Myers syndrome (SFMS), polymorphic short tandem repeats within GRIA3 gene were genotyped by PCR and denaturing polyacrylamide gel electrophoresis to test linkage between GRIA3 and the gene responsible for SFMS. The open reading frame of GRIA3 was detected for mutation by PCR amplification and direct sequencing in affected and normal males from SFMS family. One of the two short tandem repeats was informative in SFMS family. Tight linkage between SFMS locus and GRIA3 gene was established by STR3 within GRIA3 gene. No disease--causing mutation was found within the open reading frame of GRIA3 gene. The disease in SFMS family from Shandong (China) is not caused by the mutation within open reading frame of GRIA3 gene.

    Yi chuan xue bao = Acta genetica Sinica 2001;28;11;985-90

  • Granzyme B proteolysis of a neuronal glutamate receptor generates an autoantigen and is modulated by glycosylation.

    Gahring L, Carlson NG, Meyer EL and Rogers SW

    Geriatric Research Education and Clinical Center, Salt Lake City Veterans Affairs Medical Center and University of Utah School of Medicine, Salt Lake City, Utah, 84112, USA.

    Autoimmune processes are initiated when tolerance to self-proteins fails to be established or maintained and immune cells are stimulated by self-Ags. Although intracellular autoantigens are common, the origin of extracellular autoantigens is poorly defined and possibly more dangerous. In this study, we considered a mechanism for the origin of an extracellular autoantigen from the neuronal glutamate receptor subunit 3 (GluR3) in Rasmussen's encephalitis, a severe form of pediatric epilepsy. We demonstrate that specific cleavage of GluR3 by granzyme B (GB), a serine protease released by activated immune cells, can generate the GluR3B autoantigenic peptide, but only if an internal N:-linked glycosylation sequon within the GluR3-GB recognition sequence (ISND*S) is not glycosylated. However, this N:-glycon sequon while glycosylated normally is inefficiently used and glycosylation can fail. These results suggest that GB/N:-glycon sites may escape normal tolerance mechanisms and contribute to autoantibody-mediated immune diseases.

    Funded by: NINDS NIH HHS: NS35181

    Journal of immunology (Baltimore, Md. : 1950) 2001;166;3;1433-8

  • A phylogenetic analysis reveals an unusual sequence conservation within introns involved in RNA editing.

    Aruscavage PJ and Bass BL

    Department of Biochemistry/Howard Hughes Medical Institute, University of Utah, Salt Lake City 84132, USA.

    Adenosine deaminases that act on RNA (ADARs) are RNA editing enzymes that convert adenosines to inosines within cellular and viral RNAs. Certain glutamate receptor (gluR) pre-mRNAs are substrates for the enzymes in vivo. For example, at the R/G editing site of gluR-B, -C, and -D RNAs, ADARs change an arginine codon (AGA) to a glycine codon (IGA) so that two protein isoforms can be synthesized from a single encoded mRNA; the highly related gluR-A sequence is not edited at this site. To gain insight into what features of an RNA substrate are important for accurate and efficient editing by an ADAR, we performed a phylogenetic analysis of sequences required for editing at the R/G site. We observed highly conserved sequences that were shared by gluR-B, -C, and -D, but absent from gluR-A. Surprisingly, in contrast to results obtained in phylogenetic analyses of tRNA and rRNA, it was the bases in paired, helical regions whose identity was conserved, whereas bases in nonhelical regions varied, but maintained their nonhelical state. We speculate this pattern in part reflects constraints imposed by ADAR's unique specificity and gained support for our hypotheses with mutagenesis studies. Unexpectedly, we observed that some of the gluR introns were conserved beyond the sequences required for editing. The approximately 600-nt intron 13 of gluR-C was particularly remarkable, showing >94% nucleotide identity between human and chicken, organisms estimated to have diverged 310 million years ago.

    Funded by: NCI NIH HHS: 5P30CA42014; NIGMS NIH HHS: GM44073, R01 GM044073, R01 GM044073-11

    RNA (New York, N.Y.) 2000;6;2;257-69

  • Candidate gene analysis in Rett syndrome and the identification of 21 SNPs in Xq.

    Amir R, Dahle EJ, Toriolo D and Zoghbi HY

    Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.

    Rett syndrome (RTT) is an X-linked dominant neurodevelopmental disorder that affects females. Exclusion mapping studies using a new family with maternal inheritance of RTT defined Xq28 as the candidate region for the RTT gene. Six candidate genes were selected for mutation analysis based on their established expression patterns and known functions in the CNS. These are: Glutamate receptor subunit 3 (GLUR3), GABA receptor subunit alpha 3 (GABRA3), GABA receptor subunit e1 (GABRE1), Vacuolar ATPase subunit 1 (VATPS1, XAP3), the human homologue of plexin 3-SEX (XAP6) and the Synaptobrevin-like protein (SYBL1). Major rearrangements involving these genes were excluded by Southern analysis. No disease-causing mutations were found, but several single-nucleotide polymorphisms (SNPs) were detected. These SNPs will be useful in future linkage analysis and whole-genome association studies for other diseases. The genomic characterization of GLUR3 and GABRA3 will allow mutational analysis of these genes as candidates for other X-linked neurological disorders mapping to Xq25-Xq26 and Xq28.

    American journal of medical genetics 2000;90;1;69-71

  • Characterization of the human glutamate receptor subunit 3 gene (GRIA3), a candidate for bipolar disorder and nonspecific X-linked mental retardation.

    Gécz J, Barnett S, Liu J, Hollway G, Donnelly A, Eyre H, Eshkevari HS, Baltazar R, Grunn A, Nagaraja R, Gilliam C, Peltonen L, Sutherland GR, Baron M and Mulley JC

    Department of Cytogenetics and Molecular Genetics, Women's and Children's Hospital, North Adelaide, South Australia, 5006, Australia. jgecz@mad.adelaide.edu.au

    The X-chromosome breakpoint in a female patient with a balanced translocation t(X;12)(q24;q15), bipolar affective disorder and mental retardation was mapped within the glutamate receptor 3 (GRIA3) gene by fluorescence in situ hybridization. The GRIA3 cDNA of 5894 bp was cloned, and the gene structure and pattern of expression were determined. The most abundant GRIA3 transcript is composed of 17 exons. An additional 5 exons (2a, 2b, 5a, 5b, and 5c) from the 5' end of the GRIA3 open reading frame were identified by EST analysis (ESTs AI379066 and AA947914). Two new polymorphic microsatellite repeats, (TC)(n=12-26) and (AC)(n=15-19), were identified within GRIA3 5' and 3'UTRs. No mutations were detected in families segregating disorders mapping across GRIA3, one with X-linked bipolar affective disorder (BP) and one with a nonspecific X-linked mental retardation (MRX27). To assess the possibility of the involvement of the GRIA3 gene in familial cases of complex BP, a large set of 373 individuals from 40 pedigrees segregating BP were genotyped using closely linked (DXS1001) and intragenic (DXS1212 and GRIA3 3' UTR (AC)(n))) GRIA3 STR markers. No evidence of linkage was found by parametric Lod score analysis (the highest Lod score was 0. 3 at DXS1212, using the dominant transmission model) or by affected sib-pair analysis.

    Funded by: NIMH NIH HHS: MH00176, MH42535, MH43979

    Genomics 1999;62;3;356-68

  • The AMPA receptor interacts with and signals through the protein tyrosine kinase Lyn.

    Hayashi T, Umemori H, Mishina M and Yamamoto T

    Department of Oncology, Institute of Medical Science, The University of Tokyo, Japan.

    Glutamate is the major excitatory neurotransmitter in the mammalian central nervous system. The ionotropic glutamate receptors are classified into two groups, NMDA (N-methyl-D-aspartate) receptors and AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate) receptors. The AMPA receptor is a ligand-gated cation channel that mediates the fast component of excitatory postsynaptic currents in the central nervous system. Here we report that AMPA receptors function not only as ion channels but also as cell-surface signal transducers by means of their interaction with the Src-family non-receptor protein tyrosine kinase Lyn. In the cerebellum, Lyn is physically associated with the AMPA receptor and is rapidly activated following stimulation of the receptor. Activation of Lyn is independent of Ca2+ and Na+ influx through AMPA receptors. As a result of activation of Lyn, the mitogen-activated protein kinase (MAPK) signalling pathway is activated, and the expression of brain-derived neurotrophic factor (BDNF) messenger RNA is increased in a Lyn-kinase-dependent manner. Thus, AMPA receptors generate intracellular signals from the cell surface to the nucleus through the Lyn-MAPK pathway, which may contribute to synaptic plasticity by regulating the expression of BDNF.

    Nature 1999;397;6714;72-6

  • Clustering of AMPA receptors by the synaptic PDZ domain-containing protein PICK1.

    Xia J, Zhang X, Staudinger J and Huganir RL

    Department of Neuroscience, Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.

    Synaptic clustering of neurotransmitter receptors is crucial for efficient signal transduction and integration in neurons. PDZ domain-containing proteins such as PSD-95/SAP90 interact with the intracellular C termini of a variety of receptors and are thought to be important in the targeting and anchoring of receptors to specific synapses. Here, we show that PICK1 (protein interacting with C kinase), a PDZ domain-containing protein, interacts with the C termini of alpha-amino-3-hydroxy-5-methyl-isoxazole-4-propionic acid (AMPA) receptors in vitro and in vivo. In neurons, PICK1 specifically colocalizes with AMPA receptors at excitatory synapses. Furthermore, PICK1 induces clustering of AMPA receptors in heterologous expression systems. These results suggest that PICK1 may play an important role in the modulation of synaptic transmission by regulating the synaptic targeting of AMPA receptors.

    Neuron 1999;22;1;179-87

  • Novel anchorage of GluR2/3 to the postsynaptic density by the AMPA receptor-binding protein ABP.

    Srivastava S, Osten P, Vilim FS, Khatri L, Inman G, States B, Daly C, DeSouza S, Abagyan R, Valtschanoff JG, Weinberg RJ and Ziff EB

    Howard Hughes Medical Institute and Department of Biochemistry, New York University Medical Center, New York 10016, USA.

    We report the cloning of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor-binding protein (ABP), a postsynaptic density (PSD) protein related to glutamate receptor-interacting protein (GRIP) with two sets of three PDZ domains, which binds the GluR2/3 AMPA receptor subunits. ABP exhibits widespread CNS expression and is found at the postsynaptic membrane. We show that the protein interactions of the ABP/GRIP family differ from the PSD-95 family, which binds N-methyl-D-aspartate (NMDA) receptors. ABP binds to the GluR2/3 C-terminal VKI-COOH motif via class II hydrophobic PDZ interactions, distinct from the class I PSD-95-NMDA receptor interaction. ABP and GRIP also form homo- and heteromultimers through PDZ-PDZ interactions but do not bind PSD-95. We suggest that the ABP/GRIP and PSD-95 families form distinct scaffolds that anchor, respectively, AMPA and NMDA receptors.

    Funded by: NIA NIH HHS: AG13620; NINDS NIH HHS: NS29879

    Neuron 1998;21;3;581-91

  • The AMPA receptor GluR2 C terminus can mediate a reversible, ATP-dependent interaction with NSF and alpha- and beta-SNAPs.

    Osten P, Srivastava S, Inman GJ, Vilim FS, Khatri L, Lee LM, States BA, Einheber S, Milner TA, Hanson PI and Ziff EB

    Howard Hughes Medical Institute, Department of Biochemistry, NYU Medical Center, New York, New York 10016, USA.

    In this study, we demonstrate specific interaction of the GluR2 alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptor subunit C-terminal peptide with an ATPase N-ethylmaleimide-sensitive fusion protein (NSF) and alpha- and beta-soluble NSF attachment proteins (SNAPs), as well as dendritic colocalization of these proteins. The assembly of the GluR2-NSF-SNAP complex is ATP hydrolysis reversible and resembles the binding of NSF and SNAP with the SNAP receptor (SNARE) membrane fusion apparatus. We provide evidence that the molar ratio of NSF to SNAP in the GluR2-NSF-SNAP complex is similar to that of the t-SNARE syntaxin-NSF-SNAP complex. NSF is known to disassemble the SNARE protein complex in a chaperone-like interaction driven by ATP hydrolysis. We propose a model in which NSF functions as a chaperone in the molecular processing of the AMPA receptor.

    Funded by: NIA NIH HHS: AG13620; NIMH NIH HHS: MH42834

    Neuron 1998;21;1;99-110

  • AMPA receptor-mediated excitotoxicity in human NT2-N neurons results from loss of intracellular Ca2+ homeostasis following marked elevation of intracellular Na+.

    Itoh T, Itoh A, Horiuchi K and Pleasure D

    Division of Neurology, The Children's Hospital of Philadelphia, Pennsylvania 19104, USA.

    Human NT2-N neurons express Ca2+-permeable alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid glutamate receptors (AMPA-GluRs) and become vulnerable to excitotoxicity when AMPA-GluR desensitization is blocked with cyclothiazide. Although the initial increase in intracellular Ca2+ levels ([Ca2+]i) was 1.9-fold greater in the presence than in the absence of cyclothiazide, Ca2+ entry via AMPA-GluRs in an early phase of the exposure was not necessary to elicit excitotoxicity in these neurons. Rather, subsequent necrosis was caused by a >40-fold rise in [Na+]i, which induced a delayed [Ca2+]i rise. Transfer of the neurons to a 5 mM Na+ medium after AMPA-GluR activation accelerated the delayed [Ca2+]i rise and intensified excitotoxicity. Low-Na+ medium-enhanced excitotoxicity was partially blocked by amiloride or dizocilpine (MK-801), and completely blocked by removal of extracellular Ca2+, suggesting that Ca2+ entry by reverse operation of Na+/Ca2+ exchangers and via NMDA glutamate receptors was responsible for the neuronal death after excessive Na+ loading. Our results serve to emphasize the central role of neuronal Na+ loading in AMPA-GluR-mediated excitotoxicity in human neurons.

    Funded by: NINDS NIH HHS: NS08075, NS25044

    Journal of neurochemistry 1998;71;1;112-24

  • Adjacent asparagines in the NR2-subunit of the NMDA receptor channel control the voltage-dependent block by extracellular Mg2+.

    Wollmuth LP, Kuner T and Sakmann B

    Abteilung Zellphysiologie, Max-Planck-Institut für medizinische Forschung, Heidelberg, Germany. wollmuth@sunny.mpimf-Heidelberg.mpg.de

    1. The voltage-dependent block of N-methyl-D-aspartate (NMDA) receptor channels by extracellular Mg2+ is a critical determinant of its contribution to CNS synaptic physiology. The function of the narrow constriction of the channel in determining the block was investigated by analysing the effects of a set different amino acid substitutions at exposed residues positioned at or near this region. NMDA receptor channels, composed of wild-type and mutant NR1- and NR2A-subunits, were expressed in Xenopus oocytes or human embryonic kidney (HEK) 293 cells. 2. In wild-type channels, the voltage dependence (delta) of the block Mg2+ was concentration dependent with values of delta of integral of 0.82 in 0.07 mM and higher concentrations. Under bionic conditions with high extracellular Mg2+ and K+ as the reference ion, Mg2+ weakly permeated the channel. Over intermediate potentials (approximately -60 to -10 mV), this weak permeability had no apparent effect on the block but at potentials negative to approximately -60mV, it attenuated the extent and voltage dependence of the block. 3. Substitutions of glycine, serine, glutamine or aspartate for the N-site asparagine in the NR1-subunit enhanced the extent of block over intermediate potentials but left the voltage dependence of the block unchanged indicating that structural determinants of the block remained. These same substitutions either attenuated or left unchanged the apparent Mg2+ permeability. 4. In channels containing substitutions of glycine, serine or glutamine for the N-site asparagine in the NR2A-subunit, the block Mg2+ was reduced at negative potentials. Over intermediate potentials, the block was not strongly attenuated except for the glutamine substitution which reduced the voltage dependence of the block to integral of 0.57 in 0.7 mM Mg2+. 5. Equivalent substitutions for the N + 1 site asparagine in the NR2A-subunit strongly attenuated the block over the entire voltage range. In 0.7 mM Mg2+, the voltage dependence of the block was reduced to 0.50 (glycine), 0.53 (serine) and 0.46 (glutamine). 6. Channels containing substitutions of the N-site or N + 1 site asparagines in the NR2A-subunit showed an increased Mg2+ permeability suggesting that these adjacent asparagines form a barrier for inward Mg2+ flux. Changes in this barrier contribute, at least in part, to the mechanism underlying disruption of the block following substitution of these residues. 7. The adjacent NR2A-subunit asparagines are positioned at or near the narrow constriction of the channel. Pore size, however, did not determine how effectively Mg2+ blocks mutant channels. 8. It is concluded that, at the narrow constriction in the NMDA receptor channel, the adjacent NR2A-subunit asparagines, the N-site and N + 1 site, but not the N-site asparagine of the NR1-subunit, form a critical blocking site for extracellular Mg2+. The contribution to the blocking site, in contrast to the prevailing view, is stronger for the N + 1 site than for the N-site asparagine. The block may involve binding of Mg2+ to these residues.

    The Journal of physiology 1998;506 ( Pt 1);13-32

  • Differential regional distribution of AMPA receptor subunit messenger RNAs in the human spinal cord as visualized by in situ hybridization.

    Tomiyama M, Rodriguez-Puertas R, Cortés R, Christnacher A, Sommer B, Pazos A, Palacios JM and Mengod G

    Department of Neurochemistry, Instituto de Investigaciones Biomédicas de Barcelona, Consejo Superior de Investigaciones Cientificas (CSIC), Spain.

    The electrophysiological characteristics of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors vary with their subunit composition. The establishment of the subunit distribution is an essential step in the understanding of the function of these receptors. In the spinal cord, AMPA receptors are involved in normal and, possibly, pathological processes. Using in situ hybridization histochemistry with radiolabelled oligonucleotides as probes, we have studied the distribution of AMPA receptor subunit messenger RNAs (spliced flip and flop variants of glutamate receptor subunits A-D) in the human post mortem spinal cord. Transcripts for flip variants were preferentially expressed in the superficial dorsal horn, with a dorsoventral decreasing gradient of the signals. Transcripts for flop variants were also abundantly present in all layers of the gray matter, with the highest signal being observed for glutamate receptor subunit Bflop. Accordingly, flop forms were predominant in areas other than the superficial dorsal horn. This differential distribution of transcripts in the dorsal horn suggests that the subunit composition of AMPA receptors varies with the afferent inputs; AMPA receptors on neurons in the superficial dorsal horn, where terminals of thin primary afferents conducting noxious information are located, contain more flip forms, whereas neurons in the deep dorsal horn, where thick primary afferents mediating innocuous stimuli terminate, have AMPA receptors which are mainly composed of flop forms of glutamate receptor subunits A and B. The relatively high abundance of glutamate receptor subunit B transcripts in the superficial laminae of the dorsal horn indicates that AMPA receptors in these laminae have lower Ca2+ permeability. In addition, the relative abundance of glutamate receptor subunits Bflip and Dflop may show that AMPA receptors in the superficial dorsal horn have slow desensitization, while those of motor neurons have rapid desensitization.

    Neuroscience 1996;75;3;901-15

  • Human glutamate receptor hGluR3 flip and flop isoforms: cloning and sequencing of the cDNAs and primary structure of the proteins.

    Rampersad V, Elliott CE, Nutt SL, Foldes RL and Kamboj RK

    Allelix Biopharmaceuticals Inc., Mississauga, Ontario, Canada.

    Several cDNA clones encoding the human glutamate receptor subunit GluR3 flip and flop isoforms, were isolated from human hippocampus and fetal brain libraries. DNA sequence analysis revealed overlapping clones permitting the reconstruction of full-length GluR3-flip and GluR3-flop cDNAs. The GluR3 cDNAs demonstrated an 94.1-94.7% nucleotide (nt) identity with the corresponding rat cDNAs. The nt sequence of the GluR3 cDNAs would encode 894 amino acid proteins that have a 99.4% identity with the rat GluR3 isoforms. The human GluR3 cDNAs predict an additional 6 amino acid in the N-terminal signal peptide as compared to the rat GluR3.

    Biochimica et biophysica acta 1994;1219;2;563-6

  • Autoantibodies to glutamate receptor GluR3 in Rasmussen's encephalitis.

    Rogers SW, Andrews PI, Gahring LC, Whisenand T, Cauley K, Crain B, Hughes TE, Heinemann SF and McNamara JO

    Salt Lake City Geriatric Research Education and Clinical Center, Veterans Affairs Medical Center, UT.

    Rasmussen's encephalitis is a progressive childhood disease of unknown cause characterized by severe epilepsy, hemiplegia, dementia, and inflammation of the brain. During efforts to raise antibodies to recombinant glutamate receptors (GluRs), behaviors typical of seizures and histopathologic features mimicking Rasmussen's encephalitis were found in two rabbits immunized with GluR3 protein. A correlation was found between the presence of Rasmussen's encephalitis and serum antibodies to GluR3 detected by protein immunoblot analysis and by immunoreactivity to transfected cells expressing GluR3. Repeated plasma exchanges in one seriously ill child transiently reduced serum titers of GluR3 antibodies, decreased seizure frequency, and improved neurologic function. Thus, GluR3 is an autoantigen in Rasmussen's encephalitis, and an autoimmune process may underlie this disease.

    Funded by: NINDS NIH HHS: NS17771, NS28709, NS30990R29; ...

    Science (New York, N.Y.) 1994;265;5172;648-51

  • Chromosomal localization of human glutamate receptor genes.

    McNamara JO, Eubanks JH, McPherson JD, Wasmuth JJ, Evans GA and Heinemann SF

    Department of Veterans Affairs Medical Center, Durham, NC.

    The chromosomal localization of human glutamate receptor genes (GluR1-4) has been established using PCR with DNA isolated from mapping panels of Chinese hamster-human hybrid cell lines and high-resolution fluorescent in situ suppression hybridization. This was accomplished with genomic clones containing putative human homologs of rat GluR 1-4 isolated by high-stringency screening of a cosmid library with the rat cDNAs encoding GluR1-4. The locations of GluR1-4, respectively, are 5q32-33, 4q32-33, Xq25-26, and 11q22-23. Evidence implicating glutamatergic synapses in a diversity of physiologic and pathologic processes together with concordance of the chromosomal locales and results of linkage analyses establishes GluR3 and GluR4 as candidate genes for a number of nervous system disorders including the oculocerebral-renal syndrome of Lowe and a form of manic-depressive illness.

    Funded by: NHGRI NIH HHS: HG00320; NINDS NIH HHS: NS17771, NS24448; ...

    The Journal of neuroscience : the official journal of the Society for Neuroscience 1992;12;7;2555-62

  • Ca2+ permeability of KA-AMPA--gated glutamate receptor channels depends on subunit composition.

    Hollmann M, Hartley M and Heinemann S

    Molecular Neurobiology Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037.

    NMDA (N-methyl-D-aspartate) receptors and non-NMDA receptors represent the two major classes of ion channel-linked glutamate receptors. Unlike the NMDA receptor channels, non-NMDA receptor channels have usually been thought to conduct monovalent cations only. Non-NMDA receptor ion channels that can be gated by kainic acid (KA) and alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) are formed by the glutamate receptor subunits GluR1, GluR2, and GluR3. These subunits were expressed in various combinations in Xenopus oocytes so that their permeability to divalent cations could be studied. At physiological resting potentials, KA and AMPA elicited inward calcium currents in oocytes expressing GluR1, GluR3, and GluR1 plus GluR3. In contrast, oocytes expressing GluR1 plus GluR2 or GluR3 plus GluR2 showed no such permeability. Thus, in neurons expressing certain KA-AMPA receptor subunits, glutamate may trigger calcium-dependent intracellular events by activating non-NMDA receptors.

    Funded by: NINDS NIH HHS: NS28709-01

    Science (New York, N.Y.) 1991;252;5007;851-3

Gene lists (8)

Gene List Source Species Name Description Gene count
L00000009 G2C Homo sapiens Human PSD Human orthologues of mouse PSD adapted from Collins et al (2006) 1080
L00000014 G2C Homo sapiens Human ARC Human orthologues of mouse AMPA receptor complex adapted from Collins et al (2006) 9
L00000016 G2C Homo sapiens Human PSP Human orthologues of mouse PSP adapted from Collins et al (2006) 1121
L00000049 G2C Homo sapiens TAP-PSD-95-CORE TAP-PSD-95 pull-down core list (ortho) 120
L00000059 G2C Homo sapiens BAYES-COLLINS-HUMAN-PSD-CONSENSUS Human cortex PSD consensus 748
L00000061 G2C Homo sapiens BAYES-COLLINS-MOUSE-PSD-CONSENSUS Mouse cortex PSD consensus (ortho) 984
L00000069 G2C Homo sapiens BAYES-COLLINS-HUMAN-PSD-FULL Human cortex biopsy PSD full list 1461
L00000071 G2C Homo sapiens BAYES-COLLINS-MOUSE-PSD-FULL Mouse cortex PSD full list (ortho) 1556
© G2C 2014. The Genes to Cognition Programme received funding from The Wellcome Trust and the EU FP7 Framework Programmes:
EUROSPIN (FP7-HEALTH-241498), SynSys (FP7-HEALTH-242167) and GENCODYS (FP7-HEALTH-241995).

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