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

Glazner, Gordon W.; Chan, Sic L.; Lu, Chengbiao; Mattson, Mark P.

doi:10.1523/jneurosci.20-10-03641.2000

Cited by 129 publications

(101 citation statements)

References 63 publications

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“…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).…”

Section: Discussionmentioning

confidence: 94%

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

Guttmann

Sokol²,

Baker³

et al. 2002

J Pharmacol Exp Ther

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N-Methyl-D-aspartate (NMDA) receptors are calcium-permeable glutamate receptors that play putative roles in learning, memory, and excitotoxicity. NMDA receptor-mediated calcium entry can activate the calcium-dependent protease calpain, leading to substrate degradation. The major NMDA receptor 2 (NR2) subunits of the receptor are in vitro substrates for calpain at selected sites in the C-terminal region. In the present study, we assessed the ability of calpain-mediated proteolysis to modulate the NR1a/2A subtype in a heterologous expression system. Human embryonic kidney (HEK293t) cells, which endogenously express calpain, were cotransfected with NR1a/2A in addition to the calpain inhibitor calpastatin or empty vector as control. Receptor activation by glutamate and glycine as co-agonists led to calpain activation as measured by succinyl-L-leucyl-L-leucyl-L-valyl-L-tyrosyl-aminomethyl coumarin (Suc-LLVY-AMC). Calpain activation also resulted in the degradation of NR2A and decreased binding of 125 I-MK-801 ( 125 I-dizocilpine) to NR1a/2A receptors. No stable N-terminal fragment of the NMDA receptor was formed after calpain activation, suggesting calpain regulation of NMDA receptor levels in ways distinct from that previously observed with in vitro cleavage. NR2 subunit constructs lacking the final 420 amino acids were not degraded by calpain. Agonist-stimulated NR1a/2A-transfected cells also had decreased calcium uptake and produced lower changes in agonist-stimulated intracellular calcium compared with cells cotransfected with calpastatin. Calpastatin had no effect on either calcium uptake or intracellular calcium levels when the NR2A subunit lacked the final 420 amino acids. These studies demonstrate that NR2A is a substrate for calpain in situ and that this proteolytic event can modulate NMDA receptor levels.

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Section: Discussionmentioning

confidence: 94%

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

Guttmann

Sokol²,

Baker³

et al. 2002

J Pharmacol Exp Ther

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“…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.…”

Section: Neuroprotective Strategiesmentioning

confidence: 99%

Pathophysiology of Cerebral Ischemia and Brain Trauma: Similarities and Differences

Bramlett

Dietrich

2004

J Cereb Blood Flow Metab

567

358

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Summary: Current knowledge regarding the pathophysiology of cerebral ischemia and brain trauma indicates that similar mechanisms contribute to loss of cellular integrity and tissue destruction. Mechanisms of cell damage include excitotoxicity, oxidative stress, free radical production, apoptosis and inflammation. Genetic and gender factors have also been shown to be important mediators of pathomechanisms present in both injury settings. However, the fact that these injuries arise from different types of primary insults leads to diverse cellular vulnerability patterns as well as a spectrum of injury processes. Blunt head trauma produces shear forces that result in primary membrane damage to neuronal cell bodies, white matter structures and vascular beds as well as secondary injury mechanisms. Severe cerebral ischemic insults lead to metabolic stress, ionic perturbations, and a complex cascade of biochemical and molecular events ultimately causing neuronal death. Similarities in the pathogenesis of these cerebral injuries may indicate that therapeutic strategies protective following ischemia may also be beneficial after trauma. This review summarizes and contrasts injury mechanisms after ischemia and trauma and discusses neuroprotective strategies that target both types of injuries.

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“…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).…”

Section: The Intracellular Proteasesmentioning

confidence: 99%

Calcium and apoptosis: facts and hypotheses

et al. 2003

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Although longstanding experimental evidence has associated alterations of calcium homeostasis to cell death, only in the past few years the role of calcium in the signaling of apoptosis has been extensively investigated. In this review, we will summarize the current knowledge, focusing on (i) the effect of the proteins of the Bcl-2 family on ER Ca 2 þ levels, (ii) the action of the proteolytic enzymes of apoptosis on the Ca 2 þ signaling machinery, (iii) the ensuing alterations on the signaling patterns of extracellular stimuli, and (iv) the intracellular targets of 'apoptotic' Ca 2 þ signals, with special emphasis on the mitochondria and cytosolic Ca 2 þ -dependent enzymes.

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

Cited by 129 publications

References 63 publications

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

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

Pathophysiology of Cerebral Ischemia and Brain Trauma: Similarities and Differences

Calcium and apoptosis: facts and hypotheses

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