Neuronal metabotropic glutamate receptor 8 protects against neurodegeneration in CNS inflammation.

Neuronal metabotropic glutamate receptor 8 protects against neurodegeneration in CNS inflammation.

Publication date: May 03, 2021

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system with continuous neuronal loss. Treatment of clinical progression remains challenging due to lack of insights into inflammation-induced neurodegenerative pathways. Here, we show that an imbalance in the neuronal receptor interactome is driving glutamate excitotoxicity in neurons of MS patients and identify the MS risk-associated metabotropic glutamate receptor 8 (GRM8) as a decisive modulator. Mechanistically, GRM8 activation counteracted neuronal cAMP accumulation, thereby directly desensitizing the inositol 1,4,5-trisphosphate receptor (IP3R). This profoundly limited glutamate-induced calcium release from the endoplasmic reticulum and subsequent cell death. Notably, we found Grm8-deficient neurons to be more prone to glutamate excitotoxicity, whereas pharmacological activation of GRM8 augmented neuroprotection in mouse and human neurons as well as in a preclinical mouse model of MS. Thus, we demonstrate that GRM8 conveys neuronal resilience to CNS inflammation and is a promising neuroprotective target with broad therapeutic implications.

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Concepts Keywords
Endoplasmic Neuroprotection
Inflammatory Neurotransmitters
Metabotropic Metabotropic glutamate receptors
Neurodegeneration Carbonyl compounds
Neuroprotection Branches of biology
Receptor Due insights inflammation
Sclerosis Excitotoxicity
Neuron
Glutamic acid

Semantics

Type Source Name
drug DRUGBANK 1D-myo-inositol 1 4 5-trisphosphate
drug DRUGBANK Cyclic Adenosine Monophosphate
disease MESH Multiple sclerosis
disease MESH inflammation
drug DRUGBANK Calcium
pathway REACTOME Release

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