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      Structure, function, and allosteric modulation of NMDA receptors

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          Abstract

          Hansen et al. review recent structural data that have provided insight into the function and allosteric modulation of NMDA receptors.

          Abstract

          NMDA-type glutamate receptors are ligand-gated ion channels that mediate a Ca 2+-permeable component of excitatory neurotransmission in the central nervous system (CNS). They are expressed throughout the CNS and play key physiological roles in synaptic function, such as synaptic plasticity, learning, and memory. NMDA receptors are also implicated in the pathophysiology of several CNS disorders and more recently have been identified as a locus for disease-associated genomic variation. NMDA receptors exist as a diverse array of subtypes formed by variation in assembly of seven subunits (GluN1, GluN2A-D, and GluN3A-B) into tetrameric receptor complexes. These NMDA receptor subtypes show unique structural features that account for their distinct functional and pharmacological properties allowing precise tuning of their physiological roles. Here, we review the relationship between NMDA receptor structure and function with an emphasis on emerging atomic resolution structures, which begin to explain unique features of this receptor.

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          Most cited references328

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          Synaptic plasticity: multiple forms, functions, and mechanisms.

          Experiences, whether they be learning in a classroom, a stressful event, or ingestion of a psychoactive substance, impact the brain by modifying the activity and organization of specific neural circuitry. A major mechanism by which the neural activity generated by an experience modifies brain function is via modifications of synaptic transmission; that is, synaptic plasticity. Here, we review current understanding of the mechanisms of the major forms of synaptic plasticity at excitatory synapses in the mammalian brain. We also provide examples of the possible developmental and behavioral functions of synaptic plasticity and how maladaptive synaptic plasticity may contribute to neuropsychiatric disorders.
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            Developmental and regional expression in the rat brain and functional properties of four NMDA receptors.

            An in situ study of mRNAs encoding NMDA receptor subunits in the developing rat CNS revealed that, at all stages, the NR1 gene is expressed in virtually all neurons, whereas the four NR2 transcripts display distinct expression patterns. NR2B and NR2D mRNAs occur prenatally, whereas NR2A and NR2C mRNAs are first detected near birth. All transcripts except NR2D peak around P20. NR2D mRNA, present mainly in midbrain structures, peaks around P7 and thereafter decreases to adult levels. Postnatally, NR2B and NR2C transcript levels change in opposite directions in the cerebellar internal granule cell layer. In the adult hippocampus, NR2A and NR2B mRNAs are prominent in CA1 and CA3 pyramidal cells, but NR2C and NR2D mRNAs occur in different subsets of interneurons. Recombinant binary NR1-NR2 channels show comparable Ca2+ permeabilities, but marked differences in voltage-dependent Mg2+ block and in offset decay time constants. Thus, the distinct expression profiles and functional properties of NR2 subunits provide a basis for NMDA channel heterogeneity in the brain.
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              Heteromeric NMDA receptors: molecular and functional distinction of subtypes.

              The N-methyl D-aspartate (NMDA) receptor subtype of glutamate-gated ion channels possesses high calcium permeability and unique voltage-dependent sensitivity to magnesium and is modulated by glycine. Molecular cloning identified three complementary DNA species of rat brain, encoding NMDA receptor subunits NMDAR2A (NR2A), NR2B, and NR2C, which are 55 to 70% identical in sequence. These are structurally related, with less than 20% sequence identity, to other excitatory amino acid receptor subunits, including the NMDA receptor subunit NMDAR1 (NR1). Upon expression in cultured cells, the new subunits yielded prominent, typical glutamate- and NMDA-activated currents only when they were in heteromeric configurations with NR1. NR1-NR2A and NR1-NR2C channels differed in gating behavior and magnesium sensitivity. Such heteromeric NMDA receptor subtypes may exist in neurons, since NR1 messenger RNA is synthesized throughout the mature rat brain, while NR2 messenger RNA show a differential distribution.
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                Author and article information

                Journal
                J Gen Physiol
                J. Gen. Physiol
                jgp
                jgp
                The Journal of General Physiology
                Rockefeller University Press
                0022-1295
                1540-7748
                06 August 2018
                : 150
                : 8
                : 1081-1105
                Affiliations
                [1 ]Department of Biomedical and Pharmaceutical Sciences and Center for Biomolecular Structure and Dynamics, University of Montana, Missoula, MT
                [2 ]Department of Pharmacology, Emory University School of Medicine, Atlanta, GA
                [3 ]Cold Spring Harbor Laboratory, Cold Spring Harbor, NY
                [4 ]Departments of Neurobiology & Behavior and Biochemistry & Cell Biology, Stony Brook University, Stony Brook, NY
                [5 ]Department of Neuroscience, Physiology and Pharmacology, University College London, London, UK
                Author notes
                Correspondence to Stephen F. Traynelis: strayne@ 123456emory.edu
                Author information
                http://orcid.org/0000-0002-3303-4819
                http://orcid.org/0000-0002-0049-742X
                http://orcid.org/0000-0002-8179-1259
                http://orcid.org/0000-0002-3750-9615
                Article
                201812032
                10.1085/jgp.201812032
                6080888
                30037851
                a1d96e69-8c78-4d4a-b4d8-b9fd8583c4cd
                © 2018 Hansen et al.

                This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/).

                History
                : 10 May 2018
                : 03 July 2018
                Funding
                Funded by: National Institutes of Health, DOI https://doi.org/10.13039/100000002;
                Award ID: NS036654
                Award ID: NS065371
                Award ID: GM103546
                Award ID: NS097536
                Award ID: NS088479
                Categories
                Reviews
                Review
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                Anatomy & Physiology
                Anatomy & Physiology

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