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G protein–coupled receptor kinase 2 and group I metabotropic glutamate receptors mediate inflammation‐induced sensitization to excitotoxic neurodegeneration
- Degos, Vincent;
- Peineau, Stéphane;
- Nijboer, Cora;
- Kaindl, Angela M;
- Sigaut, Stéphanie;
- Favrais, Géraldine;
- Plaisant, Frank;
- Teissier, Natacha;
- Gouadon, Elodie;
- Lombet, Alain;
- Saliba, Elie;
- Collingridge, Graham L;
- Maze, Mervyn;
- Nicoletti, Ferdinando;
- Heijnen, Cobi;
- Mantz, Jean;
- Kavelaars, Annemieke;
- Gressens, Pierre
- et al.
Published Web Location
https://doi.org/10.1002/ana.23868Abstract
Objective
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-induced or interleukin (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 glutamate receptors (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) downregulation 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.Many UC-authored scholarly publications are freely available on this site because of the UC's open access policies. Let us know how this access is important for you.
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