Trends in Neurosciences
Volume 20, Issue 10, 1 October 1997, Pages 464-470
Journal home page for Trends in Neurosciences

The GluR2 (GluR-B) hypothesis: Ca2+-permeable AMPA receptors in neurological disorders

https://doi.org/10.1016/S0166-2236(97)01100-4Get rights and content

Abstract

The abnormal influx of Ca2+ through glutamate receptor channels is thought to contribute to the loss of neurons associated with a number of brain disorders. Until recently, the NMDA receptor was the only glutamate receptor known to be Ca2+-permeable. It is now well established that AMPA receptors exist not only in Ca2+-impermeable but also in Ca2+-permeable forms. AMPA receptors are encoded by four genes designated gluR1 (gluR-A) through gluR4 (gluR-D). The presence of the gluR2 subunit renders heteromeric AMPA receptor assemblies Ca2+-impermeable. Recent studies involving animal models of transient forebrain ischemia and epilepsy show that gluR2 mRNA is downregulated in vulnerable neurons. These observations suggest that downregulation of gluR2 gene expression may serve as a `molecular switch' leading to the formation of Ca2+-permeable AMPA receptors and enhanced toxicity of endogenous glutamate following a neurological insult.

Section snippets

Ca2+ permeability of AMPA receptors is controlled by the GluR2 subunit

AMPA-type glutamate receptors mediate fast excitatory synaptic transmission in the vertebrate central nervous system. AMPA receptors are ligand-gated channels that are thought to be pentamers assembled from GluR1, 2, 3 and 4 (or GluR-A, -B, -C and -D) subunits6, 7, 8 around a central aqueous pore. The predicted secondary structure of Glu-receptor subunits (Fig. 1) includes the following features: (1) a large extracellular N-terminus domain; (2) three transmembrane-spanning domains (TM1, TM3 and

Developmental regulation of Ca2+-permeable AMPA receptors

Ca2+ influx through glutamate receptors is thought to play a critical role in synaptogenesis and in the formation of neuronal circuitry during early development[45]. Because AMPA receptors might contribute to these processes, particularly at times and in cells in which NMDA receptor expression is low, an important question is whether the formation of Ca2+-permeable AMPA channels is developmentally regulated. During early postnatal life, only GluR flip splice variants are expressed in rat brain;

Ca2+-permeable AMPA receptors in global ischemia

During transient but severe global ischemia, observed in patients successfully resuscitated from cardiorespiratory arrest[52] or induced experimentally in animals53, 54, all forebrain areas are equally affected by oxygen and glucose deprivation but only selected neuronal populations degenerate and die (for a review, see [55]). Pyramidal cells in the CA1 subfield of the hippocampus are particularly vulnerable. However, histological evidence of neurodegeneration, exhibiting characteristics of

Ca2+-permeable AMPA receptors in status epilepticus

In adult rats, kainate-induced status epilepticus leads to delayed neurodegeneration of CA3 hippocampal pyramidal cells[80]. Kainic acid (administered i.p. or injected directly into the amygdala) leads to downregulation of GluR2 in the vulnerable CA3 region at times preceding significant cell loss66, 81. GluR3 is also reduced in the CA3 subfield, but to a lesser degree. gluR1 and nr1 mRNA expression are unchanged[81]. As in global ischemia, these changes in GluR expression would be expected to

Concluding remarks

This article reviews evidence that severe neurological insults such as global ischemia and limbic seizures trigger a `molecular switch' that shuts off gluR2 AMPA receptor gene expression in cells destined to die. The GluR2 hypothesis predicts that Ca2+ entry through GluR2-lacking AMPA receptors in neurons that normally express Ca2+-impermeable channels contributes to or causes delayed cell death in response to en- dogenous glutamate. In addition to their role in neurological disorders, Ca2+

Acknowledgements

We thank Flavio Moroni, Thoralf Opitz and Ricardo C. Araneda for helpful comments on this manuscript. We are grateful to Howard S. Ying and Dennis W. Choi for permission to quote unpublished data. This work was supported in part by an Italian Government grant (MURST/PNR Neurobiology) to D.E.P-G. and by National Institutes of Health Grants (NS 20752 to R.S.Z. and NS 07412 to M.V.L.B.). M.V.L.B. is the Sylvia and Robert Olnick Professor of Neuroscience.

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