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

J Neurosci Res. 2001 Aug 1;65(3):267-77. doi: 10.1002/jnr.1150.

Abstract

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).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Benzothiadiazines / pharmacology
  • Calcium / metabolism*
  • Calcium Channel Blockers / pharmacology
  • Calcium Channels / drug effects*
  • Calcium Channels / genetics
  • Calcium Channels / metabolism
  • Calcium Signaling / drug effects*
  • Cells, Cultured
  • Cerebral Cortex / cytology*
  • Dizocilpine Maleate / pharmacology
  • Excitatory Amino Acid Agonists / toxicity*
  • Excitatory Amino Acid Antagonists / pharmacology
  • Flunarizine / pharmacology
  • Gene Expression Regulation, Developmental
  • Ion Channel Gating / drug effects
  • Lanthanum / pharmacology
  • Macromolecular Substances
  • Mice
  • Nerve Tissue Proteins / drug effects*
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism
  • Neurons / drug effects*
  • Neurons / metabolism
  • Neuroprotective Agents / pharmacology
  • Nifedipine / pharmacology
  • Polyamines / pharmacology
  • Protein Subunits
  • Receptors, AMPA / biosynthesis
  • Receptors, AMPA / genetics
  • Receptors, AMPA / physiology*
  • Sodium / metabolism*
  • Sodium Channels / drug effects*
  • Sodium Channels / genetics
  • Sodium Channels / metabolism
  • Sodium-Calcium Exchanger / metabolism
  • Spermine / pharmacology
  • Tetrodotoxin / pharmacology
  • alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / toxicity*
  • omega-Conotoxins / pharmacology

Substances

  • Benzothiadiazines
  • Calcium Channel Blockers
  • Calcium Channels
  • Excitatory Amino Acid Agonists
  • Excitatory Amino Acid Antagonists
  • Macromolecular Substances
  • Nerve Tissue Proteins
  • Neuroprotective Agents
  • Polyamines
  • Protein Subunits
  • Receptors, AMPA
  • Sodium Channels
  • Sodium-Calcium Exchanger
  • omega-Conotoxins
  • omega-conotoxin-MVIIC
  • Spermine
  • Tetrodotoxin
  • Lanthanum
  • Dizocilpine Maleate
  • delta-philanthotoxin
  • alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid
  • Sodium
  • Nifedipine
  • glutamate receptor ionotropic, AMPA 2
  • cyclothiazide
  • Flunarizine
  • Calcium