Regular Article
Disruption of the GluR2-NSF Interaction Protects Primary Hippocampal Neurons from Ischemic Stress

https://doi.org/10.1006/mcne.2000.0959Get rights and content

Abstract

A specific interaction between the AMPA receptor subunits GluR2 and GluR3 and the fusion protein NSF has recently been identified. Disruption of this interaction by adenoviral-mediated expression of a peptide (pep2m) corresponding to the NSF-binding region of GluR2 results in a dramatic reduction in surface expression of AMPA receptors in primary hippocampal neurons. Here we report that expression of pep2m from a recently developed neuronal-specific adenoviral system gave significant neuroprotection to primary CA1–CA3 hippocampal neurons following stimulation with kainate (KA) and this was accompanied by a reduction in Ca2+ influx. Protection was also observed following glucose deprivation and exposure to ischemic buffer in the absence of any NMDA receptor antagonists. These results provide strong evidence that AMPA receptors play a direct role in mediating postischemic neurotoxicity.

References (41)

  • P. Osten et al.

    The AMPA receptor GluR2 C terminus can mediate a reversible, ATP-dependent interaction with NSF and alpha- and beta-SNAPs

    Neuron

    (1998)
  • D.E. Pellegrini-Giampietro et al.

    The GluR2 (GluR-B) hypothesis: Ca(2+)-permeable AMPA receptors in neurological disorders

    Trends Neurosci.

    (1997)
  • W. Pulsinelli et al.

    Antagonism of the NMDA and non-NMDA receptors in global versus focal brain ischemia

    Prog. Brain Res.

    (1993)
  • S.A. Richmond et al.

    Localization of the glutamate receptor subunit GluR1 on the surface of living and within cultured hippocampal neurons

    Neuroscience

    (1996)
  • M.J. Sheardown et al.

    AMPA, but not NMDA, receptor antagonism is neuroprotective in gerbil global ischaemia, even when delayed 24 h

    Eur. J. Pharmacol.

    (1993)
  • I. Song et al.

    Interaction of the N-ethylmaleimide-sensitive factor with AMPA receptors

    Neuron

    (1998)
  • M.J. Wagstaff et al.

    Protection of neuronal cells from apoptosis by Hsp27 delivered with a herpes simplex virus-based vector

    J. Biol. Chem.

    (1999)
  • M.V. Bennett et al.

    The GluR2 hypothesis: Ca(++)-permeable AMPA receptors in delayed neurodegeneration

    Cold Spring Harb. Symp. Quant. Biol.

    (1996)
  • A. Buchan et al.

    The N-methyl-d-aspartate antagonist, MK-801, fails to protect against neuronal damage caused by transient, severe forebrain ischemia in adult rats

    J. Neurosci.

    (1991)
  • D.W. Choi

    Calcium and excitotoxic neuronal injury

    Ann. N.Y. Acad. Sci.

    (1994)
  • Cited by (0)

    1

    To whom correspondence and reprint requests should be addressed.

    View full text