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NMDA Receptor Function
Published by Anonymous on 2007/9/30 (1644 reads)
1: Curr Drug Targets. 2007 May;8(5):633-42.


The molecular basis of conantokin antagonism of NMDA receptor function.

Prorok M, Castellino FJ.

Department of Chemistry and Biochemistry and the W. M. Keck Center for Transgene Research, University of Notre Dame, Notre Dame, Indiana 46556, USA. mprorok@nd.edu

The N-methyl-D-aspartate receptor (NMDAR), a subtype of ionotropic glutamate receptor, has been implicated in a host of chronic and acute neurological disorders. Accordingly, much emphasis has been placed on the development of safe and effective therapeutic agents that specifically antagonize this target. The conantokins are a class of small, naturally occurring peptides that inhibit ion flow through the NMDAR. Some conantokins demonstrate receptor subunit selectivity, a pharmacological attribute of emerging importance in the search for suitable drug candidates. The current review summarizes the NMDAR inhibitory properties of the conantokins, including structure-function relationships and mechanism of action. This information is fundamental to the rational design of suitable agents that can effectively treat pathophysiologies linked to NMDAR dysfunction.

Publication Types:
Review

PMID: 17504106 [PubMed - indexed for MEDLINE]

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2: Prog Neurobiol. 2007 Apr;81(5-6):272-93. Epub 2006 Dec 22.


N-methyl-D-aspartate (NMDA) receptor function and excitotoxicity in Huntington's disease.

Fan MM, Raymond LA.

Department of Psychiatry/Kinsmen Laboratories of Neurological Research, Brain Research Centre, University of British Columbia, Vancouver, BC, Canada.

Many lines of evidence support a role for neuronal damage arising as a result of excessive activation of glutamate receptors by excitatory amino acids in the pathogenesis of Huntington disease. The N-methyl-d-aspartate subclass of ionotropic glutamate receptors (NMDARs) is more selective and effective than the other subclasses in mediating this damage. As well, neurons expressing high levels of NMDARs are lost early from the striatum of individuals affected with Huntington's disease (HD), and injection of NMDAR agonists into the striatum of rodents or non-human primates recapitulates the pattern of neuronal damage observed in HD. Altered NMDAR function has been reported in corticostriatal synapses in one mouse model of HD, and NMDAR-mediated current and/or toxicity have been found to be potentiated in striatal neurons from several HD mouse models as well as heterologous cells expressing the mutant huntingtin protein. Changes in NMDAR activity have been correlated with altered calcium homeostasis, mitochondrial membrane depolarization and caspase activation. NMDAR stimulation is also closely linked to mitochondrial activity, as treatment with mitochondrial toxins has been demonstrated to produce striatal damage that can be reversed by the addition of NMDAR antagonists. Recent efforts have focused on the elucidation of molecular pathways linking huntingtin to NMDARs, as well as the mechanisms which underlie the enhancement of NMDAR activity by mutant huntingtin. Here, we review the literature to date and recent findings concerning the role of NMDARs in HD pathogenesis.

Publication Types:
Research Support, Non-U.S. Gov't
Review

PMID: 17188796 [PubMed - indexed for MEDLINE]

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3: Curr Opin Pharmacol. 2007 Feb;7(1):39-47. Epub 2006 Nov 7.


NMDA receptor subunits: function and pharmacology.

Paoletti P, Neyton J.

Laboratoire de Neurobiologie, CNRS UMR 8544 Ecole Normale Supérieure 46 rue d'Ulm, 75005 Paris, France. paoletti@biologie.ens.fr

N-methyl-D-aspartate receptors (NMDARs) are glutamate-gated ion channels widely expressed in the central nervous system that play key roles in excitatory synaptic transmission. Because of their involvement in numerous neurological disorders, NMDARs are also targets of therapeutic interest. NMDARs occur as multiple subtypes which differ in their subunit composition and in their biophysical and pharmacological properties. In particular, NMDARs contain a diversity of sites at which endogenous ligands or pharmacological agents can act to modulate receptor activity in a subunit-selective manner, and recent structural and functional data have started to reveal the molecular determinants for this subunit selectivity. These include the binding sites for glutamate, the ion-channel pore and the recently identified allosteric sites on the N-terminal domain. Other potential sites yet unexplored by medicinal chemistry programs are also considered, in particular at the interface between subunits. Given the growing body of evidence that diverse brain disorders implicate different NMDAR subtypes, such as NR2B in pain or NR3A in white matter injury, there is a growing interest in exploiting the pharmacological heterogeneity of NMDARs for the development of novel NMDAR subtype-selective compounds.

Publication Types:
Research Support, Non-U.S. Gov't
Review

PMID: 17088105 [PubMed - indexed for MEDLINE]

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4: Cell Tissue Res. 2006 Nov;326(2):439-46. Epub 2006 Jul 22.


NMDA receptor function: subunit composition versus spatial distribution.

Köhr G.

Department of Molecular Neurobiology, Max Planck Institute for Medical Research, Jahnstrasse 29, 69120 Heidelberg, Germany. kohr@mpimf-heidelberg.mpg.de

NMDA receptors (NMDARs) play a pivotal role in the regulation of neuronal communication and synaptic function in the central nervous system. The subunit composition and compartmental localization of NMDARs in neurons affect channel activity and downstream signaling. This review discusses the distinct NMDAR subtypes and their function at synaptic, perisynaptic, and extrasynaptic sites of excitatory and inhibitory neurons. Many neurons express more than one of the modulatory NR2 subunits that participate in the formation of di- and/or triheteromeric channel assemblies (e.g., NR1/NR2A, NR1/NR2B, and/or NR1/NR2A/NR2B). Depending on the subunit composition and presence or absence of intracellular binding partners along the postsynaptic membrane, these NMDAR subtypes are allocated to distinct synaptic inputs converging onto a neuron or are distributed differentially among synaptic or extrasynaptic sites. These sites can carry NR2A and NR2B subunits, supporting the hypothesis that the spatial distribution of scaffolding and signaling complexes critically determines the full spectrum of NMDAR signaling.

Publication Types:
Research Support, Non-U.S. Gov't
Review

PMID: 16862427 [PubMed - indexed for MEDLINE]

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5: Curr Top Med Chem. 2006;6(7):663-86.


NMDA receptors are not alone: dynamic regulation of NMDA receptor structure and function by neuregulins and transient cholesterol-rich membrane domains leads to disease-specific nuances of glutamate-signalling.

Schrattenholz A, Soskic V.

ProteoSys AG, Mainz, Germany. andre.schrattenholz@proteosys.com

Glutamate receptors of the N-methyl-D-asparate (NMDA-) subtype are tetrameric allosteric and ligand-gated calcium channels. They are modulated by a variety of endogenous ligands and ions and play a pivotal role in memory-related signal transduction due to a voltage-dependent block by magnesium, which makes them Hebbian coincidence detectors. On the structural level NMDA receptors have an enormous flexibility due to seven genes (NR1, NR2A-D and NR3A-B), alternative splicing, RNA-editing and extensive posttranslational modifications, like phosphorylation and glycosylation. NMDA receptors are thought to be responsible for excitotoxicity and subsequent downstream events like neuroinflammation and apoptosis and thus have been implicated in many important human pathologies, ranging from amyotrophic lateral sclerosis, Alzheimer's and Parkinson' disease, depression, epilepsy, trauma and stroke to schizophrenia. This fundamental significance of NMDA receptor-related excitotoxicity is discussed in the context of the developing clinical success of Memantine, but moreover set into relation to various proteomic and genetic markers of said diseases. The very complex localisational and functional regulation of NMDA receptors appears to be dependent on neuregulins and receptor tyrosine kinases in cholesterol-rich membrane domains (lipid rafts), calcium-related mitochondrial feedback-loops and subsynaptic structural elements like PSD-95 (post-synaptic density protein of 95 kD). The flexibility and multitude of interaction partners and possibilities of these highly dynamic molecular systems are discussed in terms of drug development strategies, in particular comparing high affinity and sub-type specific ligands to currently successful or promising therapies.

Publication Types:
Review

PMID: 16719808 [PubMed - indexed for MEDLINE]

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6: Cerebellum. 2005;4(3):162-70.


Modulation of NMDA receptors in the cerebellum. II. Signaling pathways and physiological modulators regulating NMDA receptor function.

Sanchez-Perez A, Llansola M, Cauli O, Felipo V.

Laboratory of Neurobiology, Centro de Investigacion Principe Felipe, Fundación Valenciana de Investigaciones Biomedicas, Valencia, Spain.

NMDA receptors in cerebellum have specific characteristics that make their function and modulation different from those of NMDA receptors in other brain areas. The properties of the NMDA receptor that modulate its function: Subunit composition, post-translational modifications and synaptic localization are summarized in an accompanying article. In this review we summarize how different signaling molecules modulate the function of NMDA receptors. The function of the receptors is modulated by the co-agonists glycine and serine and this modulation is different in cerebellum than in other areas. The NMDA receptor also has binding sites for polyamines that regulate its function. Other signaling molecules that modulate NMDA receptors function are: cAMP, neurotrophic factors such as BDNF, FGF-2 or neuregulins. These and other molecules allow an interplay between NMDA receptors and other receptors for neurotransmitters that may in this way modulate NMDA receptor function. This has been reported, for example, for metabotropic glutamate receptors. The expression and function of NMDA receptor is also modulated by synaptic activity, allowing an adaptation of the receptors function to the external inputs. NMDA receptors modulate important cerebral processes. NMDA receptors in different brain areas seem to modulate different processes. Cerebellar NMDA receptors play a special role in the modulation of motor learning and coordination. This is also briefly reviewed.

Publication Types:
Research Support, Non-U.S. Gov't
Review

PMID: 16147948 [PubMed - indexed for MEDLINE]

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7: Cerebellum. 2005;4(3):154-61.


Modulation of NMDA receptors in the cerebellum. 1. Properties of the NMDA receptor that modulate its function.

Llansola M, Sanchez-Perez A, Cauli O, Felipo V.

Laboratory of Neurobiology, Centro de Investigacion Principe Felipe, Fundación Valenciana de Investigaciones Biomedicas, Valencia, Spain.

NMDA receptors modulate important cerebral processes such as synaptic plasticity, long-term potentiation, learning and memory, etc. NMDA receptors in cerebellum have specific characteristics that make their function and modulation different from those of NMDA receptors in other brain areas. In this and the accompanying review we summarize the information available on the modulation of NMDA receptors in cerebellum. We review the properties of the NMDA receptor that modulate its function: subunit composition, post-translational modifications and synaptic localization. NMDA receptors are heteromeric ligand-gated ion channels assembled from two families of subunits, NR1 and NR2. There are at least eight splicing variant isoforms of the NR1 subunit and four types of NR2 subunits: NR2A, NR2B, NR2C and NR2D. NMDA receptors with different subunit composition or different splice variants of NR1 subunit have different properties. The expression of the different subunits and splicing variants varies during development. Two special characteristics of NMDA receptors in cerebellum that do not occur in other brain areas are the enrichment in the NR2C subunit and in the splice variant NR1b. As a consequence of these and other factors the pharmacology of NMDA receptors is also different in cerebellum than in other brain areas. The function and localization of NMDA receptors is also modulated by postranslational modifications including phosphorylation, glycosylation and nytrosylation. NMDA receptors are phosphorylated in serines of both NR1 and NR2 subunits and in tyrosines of NR2 subunits. Another factor modulating NMDA receptors function is the synaptic localization. The trafficking and clustering of NMDA receptors is modulated by phosphorylation and by interaction with other proteins. The signaling pathways and physiological modulators regulating NMDA receptor function as well as the role of these receptors in motor learning and coordination are reviewed in an accompanying article.

Publication Types:
Research Support, Non-U.S. Gov't
Review

PMID: 16147947 [PubMed - indexed for MEDLINE]

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8: Eur J Pharmacol. 2004 Oct 1;500(1-3):101-11.


Amino terminal domain regulation of NMDA receptor function.

Herin GA, Aizenman E.

Department of Neurobiology, University of Pittsburgh School of Medicine, E1456 BST, Pittsburgh, PA 15261, USA.

N-Methyl-D-aspartate (NMDA) receptor function is modulated by a wide variety of compounds, several of which appear to bind to globular extracellular amino terminal subunit domains (ATDs). This review focuses on modulators with putative binding sites in ATDs of NMDA receptor subunits, and potential mechanisms by which these compounds exert their effects on receptor function. With an overview that stresses several themes, we explore evidence that the ATDs of NR2 subunits appear to bind modulatory compounds in the cleft of a clamshell-like structure that is analogous to the ligand-binding domain. This modulation influences NMDA receptor function only partially, is dependent on extracellular pH, and affects receptor desensitization. Modulation of the NMDA receptor by the ATD is considered within a framework of functional modularity of multisubunit ion channels. We also consider the potential importance of the ATD in assembly of the receptor.

Publication Types:
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.
Review

PMID: 15464024 [PubMed - indexed for MEDLINE]

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9: Int Rev Neurobiol. 2004;59:491-515.


NMDA receptor function, neuroplasticity, and the pathophysiology of schizophrenia.

Coyle JT, Tsai G.

Department of Psychiatry, Harvard Medical School, McLean Hospital, Belmont, Massachusetts, USA.

Publication Types:
Review

PMID: 15006500 [PubMed - indexed for MEDLINE]

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10: Psychopharmacology (Berl). 2003 Sep;169(3-4):215-33. Epub 2003 Sep 2.


NMDA receptor antagonist effects, cortical glutamatergic function, and schizophrenia: toward a paradigm shift in medication development.

Krystal JH, D'Souza DC, Mathalon D, Perry E, Belger A, Hoffman R.

Schizophrenia Biological Research Center (116-A), VA Connecticut Healthcare System, 950 Campbell Ave., West Haven, CT 06516, USA. john.krystal@yale.edu

There is an urgent need to improve the pharmacotherapy of schizophrenia despite the introduction of important new medications. New treatment insights may come from appreciating the therapeutic implications of model psychoses. In particular, basic and clinical studies have employed the N-methyl-D-aspartate (NMDA) glutamate receptor antagonist, ketamine, as a probe of NMDA receptor contributions to cognition and behavior. These studies illustrate a translational neuroscience approach for probing mechanistic hypotheses related to the neurobiology and treatment of schizophrenia and other disorders. Two particular pathophysiologic themes associated with schizophrenia, the disturbance of cortical connectivity and the disinhibition of glutamatergic activity may be modeled by the administration of NMDA receptor antagonists. The purpose of this review is to consider the possibility that agents that attenuate these two components of NMDA receptor antagonist response may play complementary roles in the treatment of schizophrenia.

Publication Types:
Research Support, U.S. Gov't, Non-P.H.S.
Research Support, U.S. Gov't, P.H.S.
Review

PMID: 12955285 [PubMed - indexed for MEDLINE]

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11: Nihon Shinkei Seishin Yakurigaku Zasshi. 2002 Oct;22(5):165-7.


[Regulation of NMDA receptor function by Fyn-mediated tyrosine phosphorylation]

[Article in Japanese]

Nakazawa T, Tezuka T, Yamamoto T.

Division of Oncology, Institute of Medical Science, University of Tokyo, Tokyo, 108-8639 Japan.

The ionnotropic glutamate receptor, N-methyl-D-aspartate (NMDA) receptor, is a prominent ligand-gated and voltage-gated ion channel in excitatory synaptic transmission in the mammalian central nervous system. The NMDA channel is also regulated by its phosphorylation. We have shown that an Src family kinase Fyn phosphorylates NR2A and NR2B subunits of the NMDA receptor. The phosphorylation events are facilitated by the presence of PSD-95, which is quite likely due to the complex formation of Fyn, PSD-95, and the NMDA receptor: Fyn interacts with PSD-95 and PSD-95 interacts with the NMDA receptor. We have identified tyrosine phosphorylation sites on NR2A and NR2B. A phosphorylation of one of the sites on NR2B (Tyr1472) is largely dependent on Fyn and is elevated upon the LTP induction of hippocampal CA1 neurons. The data suggest that Tyr-1472 phosphorylation of NR2B is important for synaptic plasticity. A phosphorylation of the other tyrosine residues of NR2A and NR2B would also be involved in brain development and function.

Publication Types:
English Abstract
Review

PMID: 12451687 [PubMed - indexed for MEDLINE]

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12: Trends Neurosci. 2002 Sep;25(9):474-80.


Cysteine regulation of protein function--as exemplified by NMDA-receptor modulation.

Lipton SA, Choi YB, Takahashi H, Zhang D, Li W, Godzik A, Bankston LA.

Center for Neuroscience and Aging, The Burnham Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA. slipton@burnham.org

Until recently cysteine residues, especially those located extracellularly, were thought to be important for metal coordination, catalysis and protein structure by forming disulfide bonds - but they were not thought to regulate protein function. However, this is not the case. Crucial cysteine residues can be involved in modulation of protein activity and signaling events via other reactions of their thiol (sulfhydryl; -SH) groups. These reactions can take several forms, such as redox events (chemical reduction or oxidation), chelation of transition metals (chiefly Zn(2+), Mn(2+) and Cu(2+)) or S-nitrosylation [the catalyzed transfer of a nitric oxide (NO) group to a thiol group]. In several cases, these disparate reactions can compete with one another for the same thiol group on a single cysteine residue, forming a molecular switch composed of a latticework of possible redox, NO or Zn(2+) modifications to control protein function. Thiol-mediated regulation of protein function can also involve reactions of cysteine residues that affect ligand binding allosterically. This article reviews the basis for these molecular cysteine switches, drawing on the NMDA receptor as an exemplary protein, and proposes a molecular model for the action of S-nitrosylation based on recently derived crystal structures.

Publication Types:
Research Support, U.S. Gov't, P.H.S.
Review

PMID: 12183209 [PubMed - indexed for MEDLINE]

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13: Curr Drug Targets. 2001 Sep;2(3):313-22.


Structure-function relationships of the NMDA receptor antagonist conantokin peptides.

Prorok M, Castellino FJ.

Department of Chemistry and Biochemistry, and the W.M.Keck Center for Transgene Research, University of Notre Dame, Indiana 46556, USA.

The three members of the conantokin peptide family identified to date are conantokin(con)-G, -T and -R. Their defining attributes include a high relative content of gamma-carboxyglutamic acid (Gla), N-terminal sequence identity, as well as considerable overall sequence homology, and antagonism of the N-methyl-D-aspartate receptor (NMDAR). As promising templates for the design of neuroprotective agents, a thorough evaluation of structure-function relationships in these peptides will be invaluable in aiding rational drug modeling. To this end, a comprehensive assessment of the contributions of individual residues to conantokin structure and function is required. The current review summarizes recent efforts in this area, and also includes the effects of peptide length, as well as structural-stabilization and -destabilization on the structural and inhibitory profiles of an extensive panel ofconantokin derivatives.

Publication Types:
Review

PMID: 11554555 [PubMed - indexed for MEDLINE]

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14: Pharm Unserer Zeit. 2000 Jul;29(4):228-36.


[Structure, function and potential therapeutic possibilities of NMDA receptors. 2. Therapy concepts and new receptor ligands]

[Article in German]

Stark H, Reichert U, Grassmann S.

Freie Universität Berlin, Institut für Pharmazie, Germany. stark@schunet.pharmazie.fu-berlin.de

Publication Types:
Review

PMID: 10969535 [PubMed - indexed for MEDLINE]

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15: Funct Neurol. 1999 Jul-Sep;14(3):171-84.


Mitochondrial function and NMDA receptor activation: mechanisms of secondary excitotoxicity.

Greene JG.

Department of Neurology, Emory University School of Medicine, Atlanta, GA 30322, USA.

Publication Types:
Review

PMID: 10568220 [PubMed - indexed for MEDLINE]

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16: Methods Mol Biol. 1999;128:93-102.


The use of ligand binding in assays of NMDA receptor function.

Reynolds IJ, Sharma TA.

Department of Pharmacology, University of Pittsburgh, PA, USA.

Publication Types:
Review

PMID: 10320975 [PubMed - indexed for MEDLINE]

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17: Prog Brain Res. 1998;118:53-71.


Why is the role of nitric oxide in NMDA receptor function and dysfunction so controversial?

Aizenman E, Brimecombe JC, Potthoff WK, Rosenberg PA.

Department of Neurobiology, University of Pittsburgh School of Medicine, PA 15261, USA. redox+@pitt.edu

Publication Types:
Review

PMID: 9932434 [PubMed - indexed for MEDLINE]

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18: Crit Rev Neurobiol. 1998;12(3):177-204.


Developmental aspects of NMDA receptor function.

Vallano ML.

Department of Pharmacology, SUNY/Health Science Center, Syracuse, New York 13210, USA.

Glutamate is the major excitatory neurotransmitter in mammalian synapses. It binds to three classes of predominantly postsynaptic ionotropic receptors to activate receptor-associated channels, and a class of metabotropic receptors to activate G-protein mediated transduction pathways. The N-methyl-D-aspartate (NMDA) receptor (NR) is distinctive in being both ligand and voltage-gated, and selectively permeable to Ca2+. As a consequence, NR-mediated alterations in intracellular Ca2+ levels regulate a variety of signaling pathways, ranging from localized, acute effects on receptor and channel activities to long-term effects on nuclear gene transcription. Regulated expression, assembly, and modulation of distinct heteromeric NR complexes comprised of different subunit combinations contributes to this functional diversity. NRs have been implicated in several developmental processes, and evidence supporting their role in migration, survival, and synaptic maturation is discussed.

Publication Types:
Research Support, U.S. Gov't, P.H.S.
Review

PMID: 9847054 [PubMed - indexed for MEDLINE]

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19: Neuropharmacology. 1995 Oct;34(10):1219-37.


Structure and function of the NMDA receptor channel.

Mori H, Mishina M.

Department of Pharmacology, Faculty of Medicine, University of Tokyo, Japan.

Publication Types:
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.
Review

PMID: 8570021 [PubMed - indexed for MEDLINE]

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20: Trends Neurosci. 1994 Dec;17(12):536-43.


Cellular and synaptic localization of NMDA and non-NMDA receptor subunits in neocortex: organizational features related to cortical circuitry, function and disease.

Huntley GW, Vickers JC, Morrison JH.

Fishberg Research Center for Neurobiology, Mount Sinai School of Medicine, NY 10029.

Excitatory amino acid (EAA) receptors are an important component of neocortical circuitry as a result of their role as the principal mediators of excitatory synaptic activity, as well as their involvement in use-dependent modifications of synaptic efficacy, excitoxicity and cell death. The diversity in the effects generated by EAA-receptor activation can be attributed to multiple receptor subtypes, each of which is composed of multimeric assemblies of functionally distinct receptor subunits. The use of subunit-specific antibodies and molecular probes now makes it feasible to localize individual receptor subunits anatomically with a high level of cellular and synaptic resolution. Initial studies of the distribution of immunocytochemically localized EAA-receptor subunits suggest that particular subunit combinations exhibit a differential cellular, laminar and regional distribution in the neocortex. While such patterns might indicate that the functional heterogeneity of EAA-receptor-linked circuits, and the cell types in which they operate, are based partly on differential subunit parcellation, a definitive integration of these anatomical details into current schemes of cortical circuitry and organization awaits many further studies. Ideally, such studies should link a high level of molecular precision regarding subunit localization with synaptic details of identified connections and neurochemical features of neocortical cells.

Publication Types:
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.
Review

PMID: 7532339 [PubMed - indexed for MEDLINE]

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21: FASEB J. 1994 Jul;8(10):745-52.


Modulation of NMDA receptor function: implications for vertebrate neural development.

Scheetz AJ, Constantine-Paton M.

Department of Biology, Yale University, New Haven, Connecticut 06511.

The NMDA subtype of glutamate receptor is hypothesized to mediate synaptic competition in the developing brain by stabilizing converging synapses that have correlated activity patterns. Disruption of NMDA receptor function during development interferes with synapse elimination and sensory map formation. Moreover, many studies indicate that NMDA receptor function is high during times of synaptic rearrangement. In this review, a corollary of the NMDA receptor hypothesis for activity-dependent synapse stabilization is proposed. As developing inputs increase in number and strength, the increasing excitatory synaptic activity in young neurons should lead to increases in postsynaptic Ca2+ influx through NMDA receptors. This Ca2+ flux is postulated to trigger a feedback system that changes the subunit composition of the NMDA receptor complex so that less Ca2+ enters postsynaptic cells upon NMDA receptor activation. Changes in NMDA receptor effectiveness resulting from manipulations of activity are consistent with the idea that NMDA receptor function is under the control of activity. This postulate of activity-dependent control of NMDA receptor expression has implications for the control of brain plasticity. If particular combinations of NMDA receptor subunits typically expressed in young animals are better than adult receptor types at maintaining synapses in regions where they are not well correlated with other inputs, then expression of these juvenile subunit combinations could facilitate synaptic rearrangements in the mature brain after the normal end of synaptic plasticity. Thus, understanding the regulation of NMDA receptor function during development could provide a novel approach to restructuring circuitry in the adult brain to compensate for damage produced by trauma or disease.

Publication Types:
Review

PMID: 8050674 [PubMed - indexed for MEDLINE]

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22: Alcohol Alcohol Suppl. 1994;2:199-204.


Ethanol inhibition of NMDA receptor function in primary cultures of rat cerebellar granule cells and cerebral cortical cells.

Hoffman PL, Snell LD, Bhave SV, Tabakoff B.

Department of Pharmacology, University of Colorado Health Sciences Center, Denver 80262, USA.

Ethanol inhibits the function of the N-methyl-D-aspartate (NMDA) subtype of glutamate receptor in various neuronal systems, but the mechanism of the inhibition has not been elucidated. Previous work, using primary cultures of rat cerebellar granule cells, showed that both exposure to alcohol and activation of protein kinase C (PKC) by the phorbol ester PMA reduced the potency of the co-agonist, glycine, to enhance NMDA receptor function (measured as an increase in intracellular Ca2+), resulting in inhibition of the NMDA response at low glycine concentrations. Inhibition of NMDA receptor function by PMA and ethanol could also be overcome by PKC antagonists, implicating PKC in the inhibitory effect of ethanol. We have now compared the effects of ethanol and PKC activation of NMDA receptor function in primary cultures of rat cerebral cortical cells. The receptor in these cells was much less sensitive to ethanol inhibition, and the inhibition was not overcome by high concentrations of glycine. Furthermore, PMA treatment resulted in an increased response to NMDA at low glycine concentrations. The results indicate that PKC does not mediate ethanol inhibition of NMDA receptor function in cerebral cortical cells, and that the mechanism of ethanol inhibition can vary among brain regions and/or cell types. Possible determinants of the differing mechanisms of ethanol's actions include the subunit composition of the NMDA receptor and/or the isoforms of PKC present in the different cells.

Publication Types:
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.
Review

PMID: 8974336 [PubMed - indexed for MEDLINE]

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23: Prog Brain Res. 1994;102:277-85.


Regulation of N-methyl-D-aspartate (NMDA) receptor function during the rearrangement of developing neuronal connections.

Hofer M, Constantine-Paton M.

Department of Biology, Yale University, New Haven, CT 06511.

There is evidence from a number of studies that the molecular and biophysical properties of NMDA receptors are altered during normal development. A temporal correlation with changes in NMDA receptor efficacy and periods of synaptic plasticity has been demonstrated in several systems, suggesting that NMDA receptors have a critical function in determining periods of synaptic plasticity. Data from our laboratory demonstrate reduced NMDA sensitivity of the tectal evoked potential following chronic application of NMDA to the tadpole tectum, a treatment that may mimic a naturally occurring mechanism for limiting neuronal plasticity to certain stages of development. Our analysis of the expression pattern of mRNA coding for various glutamate receptor subunits in the rat retinocollicular system establishes that differential regulation of NMDA receptor subunits at the mRNA level could be a molecular basis for changes in biophysical and pharmacological properties of the NMDA receptor complex. However, even though the NMDA receptor is the best studied candidate to function as a 'plasticity switch', there are large gaps in our understanding of the complete set of factors that control the ability of synapses to rearrange during development.

Publication Types:
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.
Review

PMID: 7800818 [PubMed - indexed for MEDLINE]
 

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