Role of GluR2 expression in AMPA-induced toxicity in cultured murine cerebral cortical neurons.
alpha-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).
Jensen
J B
JB
The Royal Danish School of Pharmacy, NeuroScience PharmaBiotech Research Center, Department of Pharmacology, 2 Universitetsparken, DK-2100 Copenhagen, Denmark.
Lund
T M
TM
Timmermann
D B
DB
Schousboe
A
A
Pickering
D S
DS
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001581:Benzothiadiazines / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D002121:Calcium Channel Blockers / Q000494:pharmacology; D015220:Calcium Channels / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects*; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology*; D016291:Dizocilpine Maleate / Q000494:pharmacology; D018690:Excitatory Amino Acid Agonists / Q000633:toxicity*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005444:Flunarizine / Q000494:pharmacology; D018507:Gene Expression Regulation, Developmental; D015640:Ion Channel Gating / Q000187:drug effects; D007811:Lanthanum / Q000494:pharmacology; D046911:Macromolecular Substances; D051379:Mice; D009419:Nerve Tissue Proteins / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology; D009543:Nifedipine / Q000494:pharmacology; D011073:Polyamines / Q000494:pharmacology; D021122:Protein Subunits; D018091:Receptors, AMPA / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D012964:Sodium / Q000378:metabolism*; D015222:Sodium Channels / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D019831:Sodium-Calcium Exchanger / Q000378:metabolism; D013096:Spermine / Q000494:pharmacology; D013779:Tetrodotoxin / Q000494:pharmacology; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000633:toxicity*; D020960:omega-Conotoxins / Q000494:pharmacology
D001581:Benzothiadiazines; D002121:Calcium Channel Blockers; D015220:Calcium Channels; D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; D046911:Macromolecular Substances; D009419:Nerve Tissue Proteins; D018696:Neuroprotective Agents; D011073:Polyamines; D021122:Protein Subunits; D018091:Receptors, AMPA; D015222:Sodium Channels; D019831:Sodium-Calcium Exchanger; D020960:omega-Conotoxins; C075851:omega-conotoxin-MVIIC; D013096:Spermine; D013779:Tetrodotoxin; D007811:Lanthanum; D016291:Dizocilpine Maleate; C034092:delta-philanthotoxin; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; D012964:Sodium; D009543:Nifedipine; C104722:glutamate receptor ionotropic, AMPA 2; C004639:cyclothiazide; D005444:Flunarizine; D002118:Calcium