Ionotropic glutamate receptors (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database

  • Bernhard Bettler University of Basel
  • Graham L. Collingridge University of Bristol
  • Ray Dingledine Emory University
  • Stephen F. Heinemann Salk Institute
  • Michael Hollmann Ruhr University Bochum
  • Juan Lerma Universidad Miguel Hernández
  • David Lodge University of Bristol
  • Mark Mayer National Institutes of Health
  • Masayoshi Mishina University of Tokyo
  • Christophe Mulle Université Bordeaux 2
  • Shigetada Nakanishi Kyoto University Faculty of Medicine
  • Richard Olsen University of California Los Angels
  • Stephane Peineau University of Bristol https://orcid.org/0000-0002-4721-6795
  • John A. Peters University of Dundee https://orcid.org/0000-0002-4277-4245
  • Peter Seeburg Max Planck Institute for Medical Research
  • Michael Spedding Spedding Research Solutions SARL https://orcid.org/0000-0002-1247-8221
  • Jeffrey C. Watkins University of Bristol

Abstract


The ionotropic glutamate receptors comprise members of the NMDA (N-methyl-D-aspartate), AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid) and kainate receptor classes, named originally according to their preferred, synthetic, agonist [34, 87, 147]. Receptor heterogeneity within each class arises from the homo-oligomeric, or hetero-oligomeric, assembly of distinct subunits into cation-selective tetramers. Each subunit of the tetrameric complex comprises an extracellular amino terminal domain (ATD), an extracellular ligand binding domain (LBD), three transmembrane domains composed of three membrane spans (M1, M3 and M4), a channel lining re-entrant ‘p-loop’ (M2) located between M1 and M3 and an intracellular carboxy- terminal domain (CTD) [94, 66, 102, 147, 77]. The X-ray structure of a homomeric ionotropic glutamate receptor (GluA2 – see below) has recently been solved at 3.6Å resolution [135] and although providing the most complete structural information current available may not representative of the subunit arrangement of, for example, the heteromeric NMDA receptors [69]. It is beyond the scope of this supplement to discuss the pharmacology of individual ionotropic glutamate receptor isoforms in detail; such information can be gleaned from [34, 65, 30, 73, 41, 108, 23, 64, 147, 106, 107, 152]. Agents that discriminate between subunit isoforms are, where appropriate, noted in the tables and additional compounds that distinguish between receptor isoforms are indicated in the text below.

The classification of glutamate receptor subunits has been re-addressed by NC-IUPHAR [27]. The scheme developed recommends a nomenclature for ionotropic glutamate receptor subunits that is adopted here.

NMDA receptors
NMDA receptors assemble as obligate heteromers that may be drawn from GluN1, GluN2A, GluN2B, GluN2C, GluN2D, GluN3A and GluN3B subunits. Alternative splicing can generate eight isoforms of GluN1 with differing pharmacological properties. Various splice variants of GluN2B, 2C, 2D and GluN3A have also been reported. Activation of NMDA receptors containing GluN1 and GluN2 subunits requires the binding of two agonists, glutamate to the S1 and S2 regions of the GluN2 subunit and glycine to S1 and S2 regions of the GluN1 subunit [40, 24]. The minimal requirement for efficient functional expression of NMDA receptors in vitro is a di-heteromeric assembly of GluN1 and at least one GluN2 subunit variant, as a dimer of heterodimers arrangement in the extracellular domain [47, 94, 69]. However, more complex tri-heteromeric assemblies, incorporating multiple subtypes of GluN2 subunit, or GluN3 subunits, can be generated in vitro and occur in vivo. The NMDA receptor channel commonly has a high relative permeability to Ca2+ and is blocked, in a voltage-dependent manner, by Mg2+ such that at resting potentials the response is substantially inhibited.

AMPA and Kainate receptors
AMPA receptors assemble as homomers, or heteromers, that may be drawn from GluA1, GluA2, GluA3 and GluA4 subunits. Transmembrane AMPA receptor regulatory proteins (TARPs) of class I (i.e. γ2, γ3, γ4 and γ8) act, with variable stoichiometry, as auxiliary subunits to AMPA receptors and influence their trafficking, single channel conductance gating and pharmacology (reviewed in [42, 98, 145, 63]). Functional kainate receptors can be expressed as homomers of GluK1, GluK2 or GluK3 subunits. GluK1-3 subunits are also capable of assembling into heterotetramers (e.g. GluK1/K2; [82, 113, 112]). Two additional kainate receptor subunits, GluK4 and GluK5, when expressed individually, form high affinity binding sites for kainate, but lack function, but can form heteromers when expressed with GluK1-3 subunits (e.g. GluK2/K5; reviewed in [113, 64, 112]). Kainate receptors may also exhibit ‘metabotropic’ functions [82, 123]. As found for AMPA receptors, kainate receptors are modulated by auxiliary subunits (Neto proteins, [112, 83]). An important function difference between AMPA and kainate receptors is that the latter require extracellular Na+ and Cl- for their activation [11, 114]. RNA encoding the GluA2 subunit undergoes extensive RNA editing in which the codon encoding a p-loop glutamine residue (Q) is converted to one encoding arginine (R). This Q/R site strongly influences the biophysical properties of the receptor. Recombinant AMPA receptors lacking RNA edited GluA2 subunits are: (1) permeable to Ca2+; (2) blocked by intracellular polyamines at depolarized potentials causing inward rectification (the latter being reduced by TARPs); (3) blocked by extracellular argiotoxin and Joro spider toxins and (4) demonstrate higher channel conductances than receptors containing the edited form of GluA2 [131, 62]. GluK1 and GluK2, but not other kainate receptor subunits, are similarly edited and broadly similar functional characteristics apply to kainate receptors lacking either an RNA edited GluK1, or GluK2, subunit [82, 112]. Native AMPA and kainate receptors displaying differential channel conductances, Ca2+ permeabilites and sensitivity to block by intracellular polyamines have been identified [29, 62, 86]. GluA1-4 can exist as two variants generated by alternative splicing (termed ‘flip’ and ‘flop’) that differ in their desensitization kinetics and their desensitization in the presence of cyclothiazide which stabilises the nondesensitized state. TARPs also stabilise the non-desensitized conformation of AMPA receptors and facilitate the action of cyclothiazide [98]. Splice variants of GluK1-3 also exist which affects their trafficking [82, 112].
Published
16-Sep-2019
How to Cite
Bettler, B., Collingridge, G. L., Dingledine, R., Heinemann, S. F., Hollmann, M., Lerma, J., Lodge, D., Mayer, M., Mishina, M., Mulle, C., Nakanishi, S., Olsen, R., Peineau, S., Peters, J. A., Seeburg, P., Spedding, M. and Watkins, J. C. (2019) “Ionotropic glutamate receptors (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database”, IUPHAR/BPS Guide to Pharmacology CITE, 2019(4). doi: 10.2218/gtopdb/F75/2019.4.
Section
Summaries