Brain Research 886 2000 190–207 www.elsevier.com locate bres
Interactive report
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The AMPAR subunit GluR2: still front and center-stage
Hidenobu Tanaka, Sonja Y. Grooms, Michael V.L. Bennett, R. Suzanne Zukin
Department of Neuroscience , Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461, USA
Accepted 26 September 2000
Abstract
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Abnormal influx of Ca through AMPA-type glutamate receptors AMPARs is thought to contribute to the neuronal death associated
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with a number of brain disorders. AMPARs exist as both Ca -impermeable and Ca
-permeable channels. AMPARs are encoded by four genes designated GluR1 GluR-A through GluR4 GluR-D. The presence of the GluR2 subunit renders heteromeric AMPA receptor
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assemblies Ca -impermeable. Molecular diversity of AMPARs under physiological and pathological conditions is generated by
differential spatio-temporal patterns of GluR expression, by alternative RNA splicing and editing and by targeting and trafficking of receptor subunits at dendritic spines. The GluR2 gene is under transcriptional control by the RE1 element specific transcription factor, a
gene silencing factor which renders it neuron-specific. GluR2 transcripts are edited by ADAR2 double-stranded RNA-specific editase 1. AMPAR targeting and trafficking to spines are regulated by synaptic activity and are critical to synaptic plasticity. Recent studies
involving animal models of transient forebrain ischemia and epilepsy show that GluR2 mRNA and GluR2 subunit expression are
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downregulated in vulnerable neurons prior to cell death. Ca imaging and electrical recording from individual pyramidal neurons in
hippocampal slices reveal changes in AMPAR functional properties after ischemia. In slices from post-ischemia animals, CA1 neurons
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with robust action potentials exhibit greatly enhanced AMPA-elicited rises in intracellular Ca . Excitatory postsynaptic currents in
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post-ischemic CA1 exhibit an enhanced Ca -dependent component that appears to be mediated by Ca
-permeable AMPARs. These
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studies provide evidence for Ca influx through AMPARs in neurons destined to die. To examine whether acute GluR2 downregulation,
even in the absence of a neurological insult, can induce neuronal death, we performed knockdown experiments in rats and gerbils with antisense oligonucleotides targeted to GluR2 mRNA. GluR2 antisense oligonucleotide induced neuronal cell death of pyramidal neurons
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and enhanced pathogenicity of brief ischemic episodes. These observations provide evidence for Ca influx through AMPARs in neurons
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destined to die and implicate Ca -permeable AMPARs in the pathogenesis of ischemia-induced neuronal death.
2000 Elsevier
Science B.V. All rights reserved.
Theme : Neurotransmitters, modulators, transporters, and receptors
Topic : Excitatory amino acid receptors: ligand-gated channels
Keywords : Excitatory amino acid receptor; AMPA receptor; Calcium; Neurotoxicity; Ischemia; Seizure
1. Introduction mission and play a critical role in synaptogenesis and
formation of neuronal circuitry, as well as in synaptic Glutamate receptors mediate excitatory neurotrans-
plasticity including long-term potentiation and long-term depression. Excessive activation of glutamate receptors is
thought to contribute to the neurodegeneration following a
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Published on the World Wide Web on 30 October 2000.
wide range of neurological insults including ischemia,
Abbreviations: ADAR, Double-stranded RNA adenosine deaminase;
trauma, hypoglycemia and epileptic seizures. Chronic
AMPA, a-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid; AM-
neurodegenerative disorders such as Alzheimer’s disease,
PARs, AMPA receptors; EAA, excitatory amino acids; EPSCs, excitatory postsynaptic currents; NBQX, 2,3-dihydroxy-6-nitro-7-sulfamoylbenzo
Huntington’s chorea, AIDS encephalopathy, and amyot-
fquinoxiline; PMSF, phenylmethylsulfonyl fluoride; NSF, N-methyl-
rophic lateral sclerosis may also involve glutamate-induced
maleimide sensitive fusion protein; NRSF, neural restrictive silencing
neuronal cell death for reviews, see [28,73].
factor; REST, RE1 element specific transcription factor
Considerable interest has focused on the molecular
Corresponding author. Tel.: 11-718-430-2160; fax: 11-718-430-
mechanisms underlying glutamate receptor-mediated neu-
8932. E-mail address
: zukinaecom.yu.edu R.S. Zukin.
ronal death. Glutamate induces neuronal death by eliciting
0006-8993 00 – see front matter
2000 Elsevier Science B.V. All rights reserved. P I I : S 0 0 0 6 - 8 9 9 3 0 0 0 2 9 5 1 - 6
H . Tanaka et al. Brain Research 886 2000 190 –207
191
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a rise in intracellular free Ca , which activates a number
[42,52] voltage-dependent block by polyamines [13,32] of proteases, phospholipases and endoncleases, by gene-
and single channel conductance [141] of recombinant ration of free radicals that destroy cellular membranes by
AMPARs expressed in Xenopus oocytes and mammalian lipid peroxidations for reviews, see [27,29,122,135] and
cells. by induction of apoptosis [29]. Possible mechanisms by
AMPARs are ligand-gated channels and, by analogy to
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which glutamate could elicit a rise in intracellular Ca the nicotinic acetylcholine receptor, are thought to be
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include: 1 activation of Ca -permeable AMPA a-
tetrameric or pentameric assemblies arranged around a amino-3-hydroxy-5-methyl-4-isoazole-proprionic
acid- central aqueous pore.
type glutamate receptors AMPARs [146,148]; 2 activa- The current model of GluR subunit topology in the
tion of
group 1
metabotropic glutamate
receptors membrane includes: 1 a large extracellular amino-termi-
mGluRs, which are positively linked to inositol phos- nal domain; 2 three transmembrane-spanning domains
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phates; 3 activation of voltage-sensitive Ca channels;
TM1, TM3 and TM4; 3 a fourth amphipathic segment and or 4 de-activation of extrusion and or sequestration
TM2 that forms a channel-lining reentrant hairpin loop,
1
systems [99]. similar in structure to the pore-forming region of K
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Until recently, AMPARs were thought to be Ca -
channels [158]; 4 a binding domain for agonists formed impermeable. It is now well established that the presence
from segments of the amino-terminal domain and extracel- of the GluR2 subunit in heteromeric AMPAR assemblies
lular loop [138]; and 5 an intracellular C-terminal
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governs the permeability of AMPARs to Ca and Zn
. domain. The dominance of the GluR2 subunit in determin-
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In the adult mammalian central nervous system under ing permeability to Ca
and other divalent ions is physiological conditions, the vast majority of cells and
attributed to the presence of a positively charged arginine
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tissues express GluR2-containing, Ca -impermeable AM-
R in place of a glutamine Q residue within TM2, which PARs. Thus, a change in the level of GluR2 expression
forms the selectivity filter of AMPARs [21,57]. Although would be expected to have significant physiological conse-
most hippocampal
neurons express
predominantly quences. The relative expression of GluR2 subunit mRNA
heteromeric AMPARs, they may also express GluR1 and protein in neurons is not static but is regulated in a
homomers [80,157]. cell-specific manner during development [108] and may be
AMPARs are differentially expressed throughout neu- remodeled after seizures [38,113,114] or ischemic insult
rons of the mammalian central nervous system. Studies [38,44,111,114] and by administration of anti-psychotics
involving patch-clamp recording combined with RT-PCR
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[35] drugs of abuse [36,102] or corticosteroids [93]. Ca -
reverse transcriptase-polymerase chain reaction demon-
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permeable AMPARs are implicated in synaptogenesis and strate that AMPAR permeability to Ca
varies inversely formation of neuronal circuitry, particularly at times and in
with abundance of GluR2 mRNA in a wide range of cell
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cells in which NMDAR expression is low. Ca influx via
types Table 1. Excitatory principal neurons such as
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Ca -permeable AMPARs is thought to play a critical role
hippocampal [12] and neocortical [60] pyramidal cells and in growth cone movement and experience-dependent prun-
dentate gyrus granule cells [42] express abundant GluR2
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ing of synaptic connections during early development [81]. mRNA and exhibit low AMPAR Ca
-permeability. Thus, This article reviews recent studies that address transcrip-
a change in GluR2 expression would be expected to have tional and translation regulation and targeting and traffick-
significant physiological consequences. ing of the AMPAR subunit GluR2 under physiological and
pathological conditions, with a particular emphasis on 2.1. GluR2 RNA editing
transcriptional regulation of GluR2 in ischemia and status epilepticus.
The functionally critical arginine R residue within TM2 is not encoded by the GluR2 gene, but rather arises
by adenosine-specific RNA editing of the double-stranded
2. The AMPAR gene family pre-mRNA, which converts an adenosine residue in the
