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

✍ Scribed by Jette Bisgaard Jensen; Trine Meldgaard Lund; Daniel B. Timmermann; Arne Schousboe; Darryl S. Pickering

• Publisher: John Wiley and Sons
• Year: 2001
• Tongue: English
• Weight: 512 KB
• Volume: 65
• Category: Article
• ISSN: 0360-4012
• DOI: 10.1002/jnr.1150

✦ Synopsis

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.