Abstract
Increased glutamate-receptor-mediated Ca++ influx is considered an important factor underlying delayed neurodegeneration following ischemia or seizures. Until recently, the NMDA receptor was the only glutamate receptor known to be Ca++-permeable. It is now well established that glutamate receptors of the AMPA type, encoded by a gene family designated GluR1-GluR4, exist in both Ca++-permeable and Ca++-impermeable forms, depending on their subunit composition and degree of RNA editing. Recombinant channels assembled without GluR2 are permeable to Ca++, channels assembled with (edited) GluR2 are Ca++-impermeable. AMPA receptors in most adult neurons are hetero-oligomers containing GluR2 subunits, but some neurons have GluR2- less, Ca++-permeable receptors. The 'GluR2 hypothesis' predicts that a relative reduction in the expression of GluR2 results in enhanced Ca++ influx through newly synthesized AMPA receptors, thereby increasing neurotoxicity of endogenous glutamate. Recent observations indicate reduction in GluR2 expression and predict formation of Ca++-permeable AMPA receptors following global ischemia and kainate-induced status epilepticus; these changes are likely to be a major factor contributing to the delayed neurodegeneration that follows these pathological events. The delayed neurodegeneration appears to be primarily apoptotic. Thus, there are at least three strategies for neuroprotection: block of formation of GluR2-less receptors, which may be possible at several levels; block of the GluR2-less receptors themselves; and block of the subsequent apoptosis.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 373-384 |
| Number of pages | 12 |
| Journal | Cold Spring Harbor Symposia on Quantitative Biology |
| Volume | 61 |
| State | Published - 1996 |
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ASJC Scopus subject areas
- Agricultural and Biological Sciences(all)
- Molecular Biology
- Biochemistry, Genetics and Molecular Biology(all)
- Biochemistry
Cite this
The GluR2 hypothesis : Ca++-permeable AMPA receptors in delayed neurodegeneration. / Bennett, Michael V. L.; Pellegrini-Giampietro, D. E.; Gorter, J. A.; Aronica, E.; Connor, J. A.; Zukin, R. Suzanne.
In: Cold Spring Harbor Symposia on Quantitative Biology, Vol. 61, 1996, p. 373-384.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - The GluR2 hypothesis
T2 - Ca++-permeable AMPA receptors in delayed neurodegeneration
AU - Bennett, Michael V. L.
AU - Pellegrini-Giampietro, D. E.
AU - Gorter, J. A.
AU - Aronica, E.
AU - Connor, J. A.
AU - Zukin, R. Suzanne
PY - 1996
Y1 - 1996
N2 - Increased glutamate-receptor-mediated Ca++ influx is considered an important factor underlying delayed neurodegeneration following ischemia or seizures. Until recently, the NMDA receptor was the only glutamate receptor known to be Ca++-permeable. It is now well established that glutamate receptors of the AMPA type, encoded by a gene family designated GluR1-GluR4, exist in both Ca++-permeable and Ca++-impermeable forms, depending on their subunit composition and degree of RNA editing. Recombinant channels assembled without GluR2 are permeable to Ca++, channels assembled with (edited) GluR2 are Ca++-impermeable. AMPA receptors in most adult neurons are hetero-oligomers containing GluR2 subunits, but some neurons have GluR2- less, Ca++-permeable receptors. The 'GluR2 hypothesis' predicts that a relative reduction in the expression of GluR2 results in enhanced Ca++ influx through newly synthesized AMPA receptors, thereby increasing neurotoxicity of endogenous glutamate. Recent observations indicate reduction in GluR2 expression and predict formation of Ca++-permeable AMPA receptors following global ischemia and kainate-induced status epilepticus; these changes are likely to be a major factor contributing to the delayed neurodegeneration that follows these pathological events. The delayed neurodegeneration appears to be primarily apoptotic. Thus, there are at least three strategies for neuroprotection: block of formation of GluR2-less receptors, which may be possible at several levels; block of the GluR2-less receptors themselves; and block of the subsequent apoptosis.
AB - Increased glutamate-receptor-mediated Ca++ influx is considered an important factor underlying delayed neurodegeneration following ischemia or seizures. Until recently, the NMDA receptor was the only glutamate receptor known to be Ca++-permeable. It is now well established that glutamate receptors of the AMPA type, encoded by a gene family designated GluR1-GluR4, exist in both Ca++-permeable and Ca++-impermeable forms, depending on their subunit composition and degree of RNA editing. Recombinant channels assembled without GluR2 are permeable to Ca++, channels assembled with (edited) GluR2 are Ca++-impermeable. AMPA receptors in most adult neurons are hetero-oligomers containing GluR2 subunits, but some neurons have GluR2- less, Ca++-permeable receptors. The 'GluR2 hypothesis' predicts that a relative reduction in the expression of GluR2 results in enhanced Ca++ influx through newly synthesized AMPA receptors, thereby increasing neurotoxicity of endogenous glutamate. Recent observations indicate reduction in GluR2 expression and predict formation of Ca++-permeable AMPA receptors following global ischemia and kainate-induced status epilepticus; these changes are likely to be a major factor contributing to the delayed neurodegeneration that follows these pathological events. The delayed neurodegeneration appears to be primarily apoptotic. Thus, there are at least three strategies for neuroprotection: block of formation of GluR2-less receptors, which may be possible at several levels; block of the GluR2-less receptors themselves; and block of the subsequent apoptosis.
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M3 - Article
C2 - 9246466
AN - SCOPUS:0030429060
VL - 61
SP - 373
EP - 384
JO - Cold Spring Harbor Symposia on Quantitative Biology
JF - Cold Spring Harbor Symposia on Quantitative Biology
SN - 0091-7451
ER -