Role of GluR2 expression in AMPA‐induced toxicity in cultured murine cerebral cortical neurons

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.