Caspase-Mediated Degradation of AMPA Receptor Subunits: A Mechanism for Preventing Excitotoxic Necrosis and Ensuring Apoptosis

Abstract

Activation of ionotropic glutamate receptors of the AMPA and NMDA subtypes likely contributes to neuronal injury and death in various neurodegenerative disorders. Excitotoxicity can manifest as either apoptosis or necrosis, but the mechanisms that determine the mode of cell death are not known. We now report that levels of AMPA receptor subunits GluR-1 and GluR-4 are rapidly decreased in cultured rat hippocampal neurons undergoing apoptosis in response to withdrawal of trophic support (WTS), whereas levels of NMDA receptor subunits NR1, NR2A, and NR2B are unchanged. Exposure of isolated synaptosomal membranes to "apoptotic" cytosolic extracts resulted in rapid degradation of AMPA receptor subunits. Treatment of cells and synaptosomal membranes with the caspase inhibitors prevented degradation of AMPA receptor subunits, demonstrating a requirement for caspases in the process. Calcium responses to AMPA receptor activation were reduced after withdrawal of trophic support and enhanced after treatment with caspase inhibitors. Vulnerability of neurons to excitotoxic necrosis was decreased after withdrawal of trophic support and potentiated by treatment with caspase inhibitors. Our data indicate that caspase-mediated degradation of AMPA receptor subunits occurs during early periods of cell stress and may serve to ensure apoptosis by preventing excitotoxic necrosis.

Proteolysis of theN-Methyl-d-Aspartate Receptor by Calpain in Situ

“…Protease-mediated regulation of glutamate receptors has been proposed previously in tissue plasminogen activator regulation of NMDA receptors (Nicole et al, 2001) and AMPA receptor cleavage by calpains or caspases (Glazner et al, 2000). The proposed calpain cleavage of the NMDA receptor may be important in controlling secondary modulatory systems similar to those in AMPA receptor regulation, where caspase-mediated degradation of the AMPA receptor specifically shifts cell death from necrosis to apoptosis (Glazner et al, 2000).…”

Pathophysiology of Cerebral Ischemia and Brain Trauma: Similarities and Differences

“…An important advantage of hypothermic therapy is that it targets most of the pathomechanisms currently felt to participate in the pathogenesis of ischemic and traumatic brain injury (Dietrich et al, 1996b). This is an important concept, especially when discussing necrotic vs. apoptotic cell death mechanisms, since modulation of one death pathway may lead to enhanced cell death through other pathways (Pohl et al, 1999;Glazner et al, 2000). Thus, a lesson from preclinical and clinical data regarding neuroprotective strategies is that multiple injury mechanisms should be targeted for successful improvements in outcome.…”

Calcium and apoptosis: facts and hypotheses

“…Along the same lines, Ca 2 þ -permeable glutamate receptors of the AMPA subtype have also been described to be a target of caspase in neuronal apoptosis and Alzheimer's disease (Chan and Mattson, 1999). Their inactivation would avoid excitotoxicity and Ca 2 þ overload in neurons destined to apoptosis (Glazner et al, 2000).…”