Calpain-Mediated mGluR1α Truncation: A Key Step in Excitotoxicity

Xu, Wei; Wong, Tak Pan; Chéry, Nadège; Gaertner, Tara R.; Wang, Yu Tian; Baudry, Michel

doi:10.1016/j.neuron.2006.12.020

Cited by 149 publications

(154 citation statements)

References 42 publications

(51 reference statements)

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“…Tyr-mGluR1a is the Ct fragment of the mGluR1a subunit of the transmembrane metabotropic glutamate receptor. 134 Receptors containing the calpain-truncated mGluR1a subunit could elevate cytosolic Ca 2þ but could not activate PI 3 K-Akt signaling pathways, in contrast to uncleaved receptors. 134,135 #2.…”

Section: Monitoring Protein Fragments and Reacting To Their Accumulationmentioning

confidence: 99%

“…134 Receptors containing the calpain-truncated mGluR1a subunit could elevate cytosolic Ca 2þ but could not activate PI 3 K-Akt signaling pathways, in contrast to uncleaved receptors. 134,135 #2. Leu-NR2A is the Ct-fragment of the NR2A subunit of the transmembrane ionotropic glutamate receptor (NMDAR).…”

Section: Monitoring Protein Fragments and Reacting To Their Accumulationmentioning

confidence: 99%

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Augmented generation of protein fragments during wakefulness as the molecular cause of sleep: a hypothesis

Varshavsky

2012

Protein Science

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Despite extensive understanding of sleep regulation, the molecular-level cause and function of sleep are unknown. I suggest that they originate in individual neurons and stem from increased production of protein fragments during wakefulness. These fragments are transient parts of protein complexes in which the fragments were generated. Neuronal Ca 21 fluxes are higher during wakefulness than during sleep. Subunits of transmembrane channels and other proteins are cleaved by Ca 21 -activated calpains and by other nonprocessive proteases, including caspases and secretases. In the proposed concept, termed the fragment generation (FG) hypothesis, sleep is a state during which the production of fragments is decreased (owing to lower Ca 21 transients) while fragment-destroying pathways are upregulated. These changes facilitate the elimination of fragments and the remodeling of protein complexes in which the fragments resided. The FG hypothesis posits that a proteolytic cleavage, which produces two fragments, can have both deleterious effects and fitness-increasing functions. This (previously not considered) dichotomy can explain both the conservation of cleavage sites in proteins and the evolutionary persistence of sleep, because sleep would counteract deleterious aspects of protein fragments. The FG hypothesis leads to new explanations of sleep phenomena, including a longer sleep after sleep deprivation. Studies in the 1970s showed that ethanol-induced sleep in mice can be strikingly prolonged by intracerebroventricular injections of either Ca 21 alone or Ca 21 and its ionophore (Erickson et al., Science 1978;199:1219-1221 Harris, Pharmacol Biochem Behav 1979;10:527-534; Erickson et al., Pharmacol Biochem Behav 1980;12:651-656). These results, which were never interpreted in connection to protein fragments or the function of sleep, may be accounted for by the FG hypothesis about molecular causation of sleep.

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Section: Monitoring Protein Fragments and Reacting To Their Accumulationmentioning

confidence: 99%

Section: Monitoring Protein Fragments and Reacting To Their Accumulationmentioning

confidence: 99%

Augmented generation of protein fragments during wakefulness as the molecular cause of sleep: a hypothesis

Varshavsky

2012

Protein Science

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“…URT-based 35 S-pulse-chases were performed in a transcription-enabled rabbit reticulocyte extract, which has been extensively used to analyze the Arg/N-end rule pathway (9). Specific URT fusions were labeled with 35 S-Met/Cys for 10 min at 30°C, followed by a chase, immunoprecipitation with anti-flag antibody, SDS/PAGE, autoradiography, and quantification (Figs.…”

Section: Resultsmentioning

confidence: 99%

“…Specific URT fusions were labeled with 35 S-Met/Cys for 10 min at 30°C, followed by a chase, immunoprecipitation with anti-flag antibody, SDS/PAGE, autoradiography, and quantification (Figs. 4 and 5).…”

Section: Resultsmentioning

confidence: 99%

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Calpain-generated natural protein fragments as short-lived substrates of the N-end rule pathway

Piatkov

Liu

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Calpains are Ca 2+ -dependent intracellular proteases. We show here that calpain-generated natural C-terminal fragments of proteins that include G protein-coupled receptors, transmembrane ion channels, transcriptional regulators, apoptosis controllers, kinases, and phosphatases (Phe-GluN2a, Lys-Ica512, Arg-Ankrd2, Tyr-Grm1, Arg-Atp2b2, Glu-Bak, Arg-Igfbp2, Glu-IκBα, and Arg-cFos), are short-lived substrates of the Arg/N-end rule pathway, which targets destabilizing N-terminal residues. We also found that the identity of a fragment's N-terminal residue can change during evolution, but the residue's destabilizing activity is virtually always retained, suggesting selection pressures that favor a short half-life of the calpain-generated fragment. It is also shown that a self-cleavage of a calpain can result in an N-end rule substrate. Thus, the autoprocessing of calpains can control them by making active calpains short-lived. These and related results indicate that the Arg/N-end rule pathway mediates the remodeling of oligomeric complexes by eliminating protein fragments that are produced in these complexes through cleavages by calpains or other nonprocessive proteases. We suggest that this capability of the Arg/N-end rule pathway underlies a multitude of its previously known but mechanistically unclear functions.proteolysis | calpain substrates | ubiquitin

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G protein–coupled receptor kinase 2 and group I metabotropic glutamate receptors mediate inflammation‐induced sensitization to excitotoxic neurodegeneration

Degos

Peineau

Nijboer

et al. 2013

Annals of Neurology

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Objectives The concept of inflammation-induced sensitization is emerging in the field of perinatal brain injury, stroke, Alzheimer disease and multiple sclerosis. However, mechanisms underpinning this process remain unidentified. Methods We combined in vivo systemic lipopolysaccharide (LPS) or Interleukin-1β (IL-1β) induced sensitization of neonatal and adult rodent cortical neurons to excitotoxic neurodegeneration with in vitro IL-1β sensitization of human and rodent neurons to excitotoxic neurodegeneration. Within these inflammation-induced sensitization models we assessed metabotropic glutamatergic receptor (mGluR) signaling and regulation. Results We demonstrate for the first time that group I mGluRs mediate inflammation-induced sensitization to neuronal excitotoxicity in neonatal and adult neurons across species. Inflammation induced G protein–coupled receptor kinase 2 (GRK2) down-regulation and genetic deletion of GRK2 mimicked the sensitizing effect of inflammation on excitotoxic neurodegeneration. Thus, we identify GRK2 as a potential molecular link between inflammation and mGluR-mediated sensitization. Interpretation Collectively, our findings indicate that inflammation-induced sensitization is universal across species and ages and that group I mGluRs and GRK2 represent new avenues for neuroprotection in perinatal and adult neurological disorders.

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Calpain-Mediated mGluR1α Truncation: A Key Step in Excitotoxicity

Cited by 149 publications

References 42 publications

Augmented generation of protein fragments during wakefulness as the molecular cause of sleep: a hypothesis

Augmented generation of protein fragments during wakefulness as the molecular cause of sleep: a hypothesis

Calpain-generated natural protein fragments as short-lived substrates of the N-end rule pathway

G protein–coupled receptor kinase 2 and group I metabotropic glutamate receptors mediate inflammation‐induced sensitization to excitotoxic neurodegeneration

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