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