scispace - formally typeset
Search or ask a question
Journal ArticleDOI

Subunit Composition of Synaptic AMPA Receptors Revealed by a Single-Cell Genetic Approach

TL;DR: A functional quantification of the subunit composition of AMPARs in the CNS is provided and novel roles for AMPAR subunits in receptor trafficking are suggested and suggested.
About: This article is published in Neuron.The article was published on 2009-04-30 and is currently open access. It has received 605 citations till now. The article focuses on the topics: Silent synapse & Long-term depression.
Citations
More filters
Journal ArticleDOI
TL;DR: This review discusses International Union of Basic and Clinical Pharmacology glutamate receptor nomenclature, structure, assembly, accessory subunits, interacting proteins, gene expression and translation, post-translational modifications, agonist and antagonist pharmacology, allosteric modulation, mechanisms of gating and permeation, roles in normal physiological function, as well as the potential therapeutic use of pharmacological agents acting at glutamate receptors.
Abstract: The mammalian ionotropic glutamate receptor family encodes 18 gene products that coassemble to form ligand-gated ion channels containing an agonist recognition site, a transmembrane ion permeation pathway, and gating elements that couple agonist-induced conformational changes to the opening or closing of the permeation pore. Glutamate receptors mediate fast excitatory synaptic transmission in the central nervous system and are localized on neuronal and non-neuronal cells. These receptors regulate a broad spectrum of processes in the brain, spinal cord, retina, and peripheral nervous system. Glutamate receptors are postulated to play important roles in numerous neurological diseases and have attracted intense scrutiny. The description of glutamate receptor structure, including its transmembrane elements, reveals a complex assembly of multiple semiautonomous extracellular domains linked to a pore-forming element with striking resemblance to an inverted potassium channel. In this review we discuss International Union of Basic and Clinical Pharmacology glutamate receptor nomenclature, structure, assembly, accessory subunits, interacting proteins, gene expression and translation, post-translational modifications, agonist and antagonist pharmacology, allosteric modulation, mechanisms of gating and permeation, roles in normal physiological function, as well as the potential therapeutic use of pharmacological agents acting at glutamate receptors.

3,044 citations

Journal ArticleDOI
10 Dec 2009-Nature
TL;DR: The crystal structure of the α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)-sensitive, homotetrameric, rat GluA2 receptor is reported at 3.6 Å resolution in complex with a competitive antagonist to exploit mechanisms of ion channel activation, desensitization and inhibition by non-competitive antagonists and pore blockers.
Abstract: Ionotropic glutamate receptors mediate most excitatory neurotransmission in the central nervous system and function by opening a transmembrane ion channel upon binding of glutamate. Despite their crucial role in neurobiology, the architecture and atomic structure of an intact ionotropic glutamate receptor are unknown. Here we report the crystal structure of the alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)-sensitive, homotetrameric, rat GluA2 receptor at 3.6 A resolution in complex with a competitive antagonist. The receptor harbours an overall axis of two-fold symmetry with the extracellular domains organized as pairs of local dimers and with the ion channel domain exhibiting four-fold symmetry. A symmetry mismatch between the extracellular and ion channel domains is mediated by two pairs of conformationally distinct subunits, A/C and B/D. Therefore, the stereochemical manner in which the A/C subunits are coupled to the ion channel gate is different from the B/D subunits. Guided by the GluA2 structure and site-directed cysteine mutagenesis, we suggest that GluN1 and GluN2A NMDA (N-methyl-d-aspartate) receptors have a similar architecture, with subunits arranged in a 1-2-1-2 pattern. We exploit the GluA2 structure to develop mechanisms of ion channel activation, desensitization and inhibition by non-competitive antagonists and pore blockers.

952 citations

Journal ArticleDOI
14 Jan 2010-Neuron
TL;DR: It is found that the modest overexpression of alpha-synuclein, in the range predicted for gene multiplication and in the absence of overt toxicity, markedly inhibits neurotransmitter release.

938 citations


Cites methods from "Subunit Composition of Synaptic AMP..."

  • ...by whole cell recording, also as previously described (Lu et al., 2009)....

    [...]

  • ...Slices from transgenic mice and wild-type littermates were interleaved, and the experimenter was blind to genotype. mEPSCs were monitored by whole cell recording, also as previously described (Lu et al., 2009)....

    [...]

  • ...Transverse 300–400 mm hippocampal slices were prepared from 24- to 36-dayold animals hemizygous for the human asyn transgene and from wild-type littermates, and field EPSPs evoked in CA1 stratum as previously described (Lu et al., 2009)....

    [...]

Journal ArticleDOI
30 Oct 2013-Neuron
TL;DR: The progress over the last two and a half decades is reviewed, the future challenges in the field are discussed and a large number of proteins have been identified that regulate this complex process.

783 citations


Cites background from "Subunit Composition of Synaptic AMP..."

  • ...The major forms of receptors in the hippocampus include GluA1/2 and GluA2/3 heteromers as well as GluA1 homomers (Lu et al., 2009; Wenthold et al., 1996)....

    [...]

Journal ArticleDOI
21 Jun 2012-Nature
TL;DR: Glypicans is identified as a family of novel astrocyte-derived molecules that are necessary and sufficient to promote glutamate receptor clustering and receptivity and to induce the formation of postsynaptically functioning CNS synapses.
Abstract: In the developing central nervous system (CNS), the control of synapse number and function is critical to the formation of neural circuits. We previously demonstrated that astrocyte-secreted factors powerfully induce the formation of functional excitatory synapses between CNS neurons. Astrocyte-secreted thrombospondins induce the formation of structural synapses, but these synapses are postsynaptically silent. Here we use biochemical fractionation of astrocyte-conditioned medium to identify glypican 4 (Gpc4) and glypican 6 (Gpc6) as astrocyte-secreted signals sufficient to induce functional synapses between purified retinal ganglion cell neurons, and show that depletion of these molecules from astrocyte-conditioned medium significantly reduces its ability to induce postsynaptic activity. Application of Gpc4 to purified neurons is sufficient to increase the frequency and amplitude of glutamatergic synaptic events. This is achieved by increasing the surface level and clustering, but not overall cellular protein level, of the GluA1 subunit of the AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) glutamate receptor (AMPAR). Gpc4 and Gpc6 are expressed by astrocytes in vivo in the developing CNS, with Gpc4 expression enriched in the hippocampus and Gpc6 enriched in the cerebellum. Finally, we demonstrate that Gpc4-deficient mice have defective synapse formation, with decreased amplitude of excitatory synaptic currents in the developing hippocampus and reduced recruitment of AMPARs to synapses. These data identify glypicans as a family of novel astrocyte-derived molecules that are necessary and sufficient to promote glutamate receptor clustering and receptivity and to induce the formation of postsynaptically functioning CNS synapses.

589 citations

References
More filters
Journal Article
TL;DR: The cloning of cDNAs encoding glutamate receptor subunits, which occurred mainly between 1989 and 1992, stimulated the development of ionotropic glutamate receptors in the brain.
Abstract: The ionotropic glutamate receptors are ligand-gated ion channels that mediate the vast majority of excitatory neurotransmission in the brain. The cloning of cDNAs encoding glutamate receptor subunits, which occurred mainly between 1989 and 1992 ([Hollmann and Heinemann, 1994][1]), stimulated this

4,112 citations


"Subunit Composition of Synaptic AMP..." refers background in this paper

  • ...D) (Collingridge et al., 2008), contribute to the formation of heterotetrameric receptors (Dingledine et al., 1999; Hollmann and Heinemann, 1994; Mayer and Armstrong, 2004; Seeburg, 1993)....

    [...]

  • ..., 2008), contribute to the formation of heterotetrameric receptors (Dingledine et al., 1999; Hollmann and Heinemann, 1994; Mayer and Armstrong, 2004; Seeburg, 1993)....

    [...]

Journal ArticleDOI
TL;DR: The application of molecular cloning technology to the study of the glutamate receptor system has led to an explosion of knowledge about the structure, expression, and function of this most important fast excitatory transmitter system in the mammalian brain.
Abstract: The application of molecular cloning technology to the study of the glutamate receptor system has led to an explosion of knowledge about the structure, expression, and function of this most important fast excitatory transmitter system in the mammalian brain. The first functional ionotropic glutamate receptor was cloned in 1989 (Hollmann et al 1989) , and the results of this molecular-based approach over the past three years are the focus of this review. We discuss the implications of and the new questions raised by this work-which is probably only a glance at this fascinating and complex signaling system found in brains from the snails to man. Glutamate receptors are found throughout the mammalian brain, where they constitute the major excitatory transmitter system. The longest-known and best-studied glutamate receptors are ligand-gated ion channels, also called ionotropic glutamate receptors , which are permeable to cations. They have traditionally been classified into three broad subtypes based upon pharmaco­ logical and electrophysiological data: a-amino-3-hydroxy-5-methyl-4isoxazole propionate (AMPA) receptors, kainate (KA) receptors , and N-methyl-D-aspartate (NMDA) receptors. Recently, however, a family of G protein-coupled glutamate receptors , which are also called metabotropic glutamate or transl -aminocyclopentanel ,3-dicarboxylate (tACPD) recep­ tors, was identified (Sugiyama et al 1987) . (For reviews of the classification and the pharmacological and electrophysiological properties of glutamate receptors see Mayer & Westbrook 1987, Collingridge & Lester 1989, Honore 1989, Monaghan et al 1989, Wroblewski & Danysz 1 989, Hansen &

4,079 citations


"Subunit Composition of Synaptic AMP..." refers background in this paper

  • ...D) (Collingridge et al., 2008), contribute to the formation of heterotetrameric receptors (Dingledine et al., 1999; Hollmann and Heinemann, 1994; Mayer and Armstrong, 2004; Seeburg, 1993)....

    [...]

  • ...It has long been known that edited GluA2 subunits, unlike other subunits, produce very small currents as homomeric channels in heterologous expression systems (Burnashev et al., 1992; Hollmann and Heinemann, 1994)....

    [...]

  • ..., 2008), contribute to the formation of heterotetrameric receptors (Dingledine et al., 1999; Hollmann and Heinemann, 1994; Mayer and Armstrong, 2004; Seeburg, 1993)....

    [...]

Journal ArticleDOI
TL;DR: The growing literature that supports a critical role for AMPA receptors trafficking in LTP and LTD is reviewed, focusing on the roles proposed for specific AMPA receptor subunits and their interacting proteins.
Abstract: Activity-dependent changes in synaptic function are believed to underlie the formation of memories. Two prominent examples are long-term potentiation (LTP) and long-term depression (LTD), whose mechanisms have been the subject of considerable scrutiny over the past few decades. Here we review the growing literature that supports a critical role for AMPA receptor trafficking in LTP and LTD, focusing on the roles proposed for specific AMPA receptor subunits and their interacting proteins. While much work remains to understand the molecular basis for synaptic plasticity, recent results on AMPA receptor trafficking provide a clear conceptual framework for future studies.

2,587 citations


"Subunit Composition of Synaptic AMP..." refers background or result in this paper

  • ...In contrast, a number of studies have suggested that the GluA2 subunit dictates the removal of AMPARs from the synapse during LTD (Bredt and Nicoll, 2003; Collingridge et al., 2004; Malinow and Malenka, 2002; Shepherd and Huganir, 2007)....

    [...]

  • ...Since the discovery of silent synapses, AMPAR trafficking has been a leading molecular mechanism underlying synaptic plasticity (Bredt and Nicoll, 2003; Kerchner and Nicoll, 2008; Malinow and Malenka, 2002; Shepherd and Huganir, 2007)....

    [...]

  • ...Implications for AMPAR Trafficking Since the discovery of silent synapses, AMPAR trafficking has been a leading molecular mechanism underlying synaptic plasticity (Bredt and Nicoll, 2003; Kerchner and Nicoll, 2008; Malinow and Malenka, 2002; Shepherd and Huganir, 2007)....

    [...]

  • ...However, previous genetic evidence does not support a necessary role of GluA1 and GluA2 in LTP and LTD, respectively....

    [...]

  • ...As has been reported before, the I/Vs of AMPAR EPSCs are near linear (Adesnik and Nicoll, 2007; Bredt and Nicoll, 2003; Hestrin et al., 1990; Malinow and Malenka, 2002; Shepherd and Huganir, 2007), suggesting that virtually all synaptic AMPARs contain the GluA2 subunit....

    [...]

Journal ArticleDOI
24 Mar 2000-Science
TL;DR: Results show that LTP and CaMKII activity drive AMPA-Rs to synapses by a mechanism that requires the association between GluR1 and a PDZ domain protein.
Abstract: To elucidate mechanisms that control and execute activity-dependent synaptic plasticity, alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate receptors (AMPA-Rs) with an electrophysiological tag were expressed in rat hippocampal neurons. Long-term potentiation (LTP) or increased activity of the calcium/calmodulin-dependent protein kinase II (CaMKII) induced delivery of tagged AMPA-Rs into synapses. This effect was not diminished by mutating the CaMKII phosphorylation site on the GluR1 AMPA-R subunit, but was blocked by mutating a predicted PDZ domain interaction site. These results show that LTP and CaMKII activity drive AMPA-Rs to synapses by a mechanism that requires the association between GluR1 and a PDZ domain protein.

1,550 citations


"Subunit Composition of Synaptic AMP..." refers background in this paper

  • ...Based on a variety of experiments in which GluA subunits were overexpressed in culture preparations, a leading model for constitutive and activity-dependent AMPAR trafficking has been advanced (Hayashi et al., 2000; Malinow and Malenka, 2002; Passafaro et al., 2001; Shi et al., 2001)....

    [...]

Journal ArticleDOI
04 Oct 1991-Cell
TL;DR: It is shown that the genomic DNA sequences encoding the particular channel segment of all subunits harbor a glutamine codon (CAG), even though an arginine codon is found in mRNAs of three subunits.

1,445 citations


"Subunit Composition of Synaptic AMP..." refers background in this paper

  • ...This unique property, conferred by the presence of the GluA2 subunit, is due to the Arg607 residue introduced into the GluA2 pore loop by RNA editing at the Q/R site (Sommer et al., 1991)....

    [...]