The GluR2 hypothesis

Ca++-permeable AMPA receptors in delayed neurodegeneration

Michael V. L. Bennett, D. E. Pellegrini-Giampietro, J. A. Gorter, E. Aronica, J. A. Connor, R. Suzanne Zukin

Research output: Contribution to journalArticle

69 Citations (Scopus)

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 languageEnglish (US)
Pages (from-to)373-384
Number of pages12
JournalCold Spring Harbor Symposia on Quantitative Biology
Volume61
StatePublished - 1996

Fingerprint

AMPA Receptors
Glutamate Receptors
receptors
Neurons
Ischemia
RNA Editing
alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid
Status Epilepticus
Kainic Acid
N-Methyl-D-Aspartate Receptors
Oligomers
ischemia
Glutamic Acid
Seizures
Genes
RNA
Apoptosis
neurons
RNA editing
neurotoxicity

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 journalArticle

Bennett, Michael V. L. ; Pellegrini-Giampietro, D. E. ; Gorter, J. A. ; Aronica, E. ; Connor, J. A. ; Zukin, R. Suzanne. / The GluR2 hypothesis : Ca++-permeable AMPA receptors in delayed neurodegeneration. In: Cold Spring Harbor Symposia on Quantitative Biology. 1996 ; Vol. 61. pp. 373-384.
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