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Role of GluR2 expression in AMPA‐induced toxicity in cultured murine cerebral cortical neurons
Author(s) -
Jensen Jette Bisgaard,
Lund Trine Meldgaard,
Timmermann Daniel B.,
Schousboe Arne,
Pickering Darryl S.
Publication year - 2001
Publication title -
journal of neuroscience research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.72
H-Index - 160
eISSN - 1097-4547
pISSN - 0360-4012
DOI - 10.1002/jnr.1150
Subject(s) - ampa receptor , nmda receptor , glutamate receptor , neurotoxicity , chemistry , toxicity , biophysics , biology , receptor , biochemistry , organic chemistry
Abstract α‐Amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid receptor (AMPA‐R)‐mediated neurotoxicity was studied in relation to subunit expression and the presence of Ca 2+ ‐permeable receptor channels. AMPA‐mediated toxicity had two components: 1) a direct AMPA‐R‐mediated component, which was not due to Ca 2+ influx through voltage‐gated Ca 2+ channels, reversal of the Na + /Ca 2+ exchanger or release of calcium from dantrolene‐sensitive intracellular Ca 2+ stores, and 2) a minor, indirect component involving activation of NMDA receptor channels, because of glutamate release and removal of the Mg 2+ block of the NMDA receptor on AMPA‐R stimulation. The involvement of Ca 2+ influx through AMPA‐R was also examined. The number of neurons possessing Ca 2+ ‐permeable AMPA‐R increased during culture development, concurrently with an increasing susceptibility for AMPA‐induced toxicity during development. GluR2( R ) levels also increased during development, and channel blockers of Ca 2+ ‐permeable AMPA‐R lacking the GluR2( R ) subunit (spermine and philanthotoxin) failed to prevent neurotoxicity or increases in [Ca 2+ ] i . Thus, the direct AMPA‐R‐mediated toxicity may be explained by initiation of cell death by Ca 2+ fluxing through AMPA‐R containing GluR2( R ). The components of direct AMPA‐R‐mediated toxicity are proposed to be 1) toxicity mediated by GluR2( R )‐lacking AMPA‐R and 2) toxicity mediated by low‐Ca 2+ ‐permeability AMPA‐R containing GluR2( R ). J. Neurosci. Res. 65:267–277, 2001. © 2001 Wiley‐Liss, Inc.