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AMPA receptors are glutamate receptors that are tetramers of various combinations of GluR1-4 subunits. AMPA receptors containing GluR1, 3 and 4 are Ca2+ permeable, however, AMPA receptors containing even a single subunit of GluR2 are Ca2+ impermeable. Most AMPA receptors are Ca2+ impermeable due to the presence of GluR2. GluR2 confers special properties on AMPA receptors through the presence of arginine at the pore apex; other subunits (GluR1, 3, 4) contain glutamine at the pore apex and allow Ca2+ influx. Normally, an RNA editing step changes DNA-encoded glutamine to arginine, introduces arginine in the GluR2 pore apex. GluR2 RNA editing is carried out by an RNA-dependent adenosine deaminase (ADAR2). Loss of GluR2 editing leads to the formation of highly excitotoxic AMPA channels [Mahajan and Ziff (2007) Mol Cell Neurosci 35:470-481] and is shown to contribute to loss of motor neurons in amyotrophic lateral sclerosis (ALS). Relatively higher levels of Ca2+-permeable AMPA receptors are found in motor neurons and this has been correlated with lower GluR2 mRNA levels. However, the reason for loss of GluR2 editing is not known. Here we show that exposure of neurons to excitotoxic levels of glutamate leads to specific cleavage of ADAR2 that leads to generation of unedited GluR2. We demonstrate that cleaved ADAR2 leads to a decrease or loss of GluR2 editing, which will further result in high Ca2+ influx and excitotoxic neuronal death. |
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