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Start Over Descriptor "GluN3" Topic glycine
4 results on '"GluN3"'

1. Glycine agonism in ionotropic glutamate receptors.

Author

Stroebel D, Mony L, and Paoletti P

Subjects
Animals, Binding Sites, Glutamic Acid metabolism, Humans, Ligands, Mice, Receptors, N-Methyl-D-Aspartate metabolism, Serine metabolism, Synaptic Transmission physiology, Xenopus laevis metabolism, Glycine agonists, Receptors, Ionotropic Glutamate physiology
Abstract

Ionotropic glutamate receptors (iGluRs) are ligand-gated ion channels that mediate the majority of excitatory neurotransmission in the vertebrate CNS. Classified as AMPA, kainate, delta and NMDA receptors, iGluRs are central drivers of synaptic plasticity widely considered as a major cellular substrate of learning and memory. Surprisingly however, five out of the eighteen vertebrate iGluR subunits do not bind glutamate but glycine, a neurotransmitter known to mediate inhibitory neurotransmission through its action on pentameric glycine receptors (GlyRs). This is the case of GluN1, GluN3A, GluN3B, GluD1 and GluD2 subunits, all also binding the D amino acid d-serine endogenously present in many brain regions. Glycine and d-serine action and affinities broadly differ between glycinergic iGluR subtypes. On 'conventional' GluN1/GluN2 NMDA receptors, glycine (or d-serine) acts in concert with glutamate as a mandatory co-agonist to set the level of receptor activity. It also regulates the receptor's trafficking and expression independently of glutamate. On 'unconventional' GluN1/GluN3 NMDARs, glycine acts as the sole agonist directly triggering opening of excitatory glycinergic channels recently shown to be physiologically relevant. On GluD receptors, d-serine on its own mediates non-ionotropic signaling involved in excitatory and inhibitory synaptogenesis, further reinforcing the concept of glutamate-insensitive iGluRs. Here we present an overview of our current knowledge on glycine and d-serine agonism in iGluRs emphasizing aspects related to molecular mechanisms, cellular function and pharmacological profile. The growing appreciation of the critical influence of glycine and d-serine on iGluR biology reshapes our understanding of iGluR signaling diversity and complexity, with important implications in neuropharmacology., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Published
2021
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4. The GluN3 subunit regulates ion selectivity within native N-methyl-d-aspartate receptors

Author

Thomas Sullenberger, Sanjay Kumar, and Stephen Beesley

Subjects
0301 basic medicine, Protein subunit, GluN3, Triheteromeric NMDA receptors, Article, lcsh:RC321-571, 03 medical and health sciences, Glutamatergic, 0302 clinical medicine, mental disorders, Ion selectivity, Binding site, Receptor, Ion-substitution experiments, lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry, Entorhinal cortex, chemistry.chemical_classification, biology, General Neuroscience, musculoskeletal, neural, and ocular physiology, Glutamate receptor, GRIN1, Somatosensory cortex, Amino acid, Electrophysiology, 030104 developmental biology, chemistry, nervous system, Glycine, biology.protein, Biophysics, 030217 neurology & neurosurgery
Abstract

Highlights • The GluN3 subunit is the least understood of all subunits that make up functional NMDARs in the brain. • We show through ion substitution experiments that NMDARs containing GluN3 are more permeable to Ca2+ than those containing just GluN1 and GluN2. • We attribute these differences to their ability to screen for Ca2+ over Na+. • Subunit-dependent cation selectivity represents a hitherto unrealized mechanism for finer control of Ca2+ influx enhancing the repertoire of synaptic NMDARs., Glutamatergic N-methyl-d-aspartate receptors (NMDARs) are heterotetrameric proteins whose subunits are derived from three gene families, GRIN1 (codes for GluN1), GRIN2 (GluN2) and GRIN3 (GluN3). In addition to providing binding sites for glutamate and the co-agonist glycine, these subunits in their di (d-) and tri (t-) heteromeric configurations regulate various aspects of receptor function in the brain. For example, the decay kinetics of NMDAR-mediated synaptic currents depend on the type of GluN2 subunit (GluN2A-GluN2D) in the receptor subunit composition. While much is known about the contributions of GluN1 and GluN2 to d-NMDAR function, we know comparatively little about how GluN3 influences the function of t-NMDARs composed of one or more subunits from each of the three gene families. We report here that in addition to altering kinetics and voltage-dependent properties, the GluN3 subunit endows these receptors with ion selectivity wherein influx of Ca2+ is preferred over Na+. This became apparent in the process of assessing Ca2+ permeability through these receptors and is of significance given that NMDARs are generally believed to be nonselective to cations and increased selectivity can lead to enhanced permeability. This was true of two independent brain regions where t-NMDARs are expressed, the somatosensory cortex, where both receptor subtypes are expressed at separate inputs onto single neurons, and the entorhinal cortex, where they are co-expressed at individual synaptic inputs. Based on this data and the sequence of amino acids lining selectivity filters within these subunits, we propose GluN3 to be a regulatory subunit for ion selectivity in t-NMDARs.

Published
2020

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