Role of metabotropic glutamate receptor 5 signaling and homer in oxygen glucose deprivation-mediated astrocyte apoptosis

Feb 15, 2013Molecular brain

How a specific brain receptor and its partner affect star-shaped brain cell death during low oxygen and glucose conditions

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Abstract

Oxygen glucose deprivation induced both necrotic and apoptotic cell death in mouse cortical astrocytes.

Oxygen glucose deprivation increased mGluR5 protein expression and inositol phosphate formation in astrocytes.
Inhibition of mGluR5 with a selective antagonist blocked inositol phosphate formation but did not prevent necrotic cell death.
Astrocytes lacking mGluR5 were resistant to apoptosis caused by oxygen glucose deprivation but still underwent necrotic cell death.
Blocking the inositol 1,4,5 trisphosphate receptor reduced apoptotic cell death in wild-type astrocytes, but had no effect in mGluR5 knockout astrocytes.
Disruption of interactions between Homer proteins and mGluR5 also led to a reduction in astrocyte apoptosis.

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BACKGROUND: Group I metabotropic glutamate receptors (mGluR) are coupled via Gαq/11 to the activation of phospholipase Cβ, which hydrolyzes membrane phospholipids to form inositol 1,4,5 trisphosphate and diacylglycerol. In addition to functioning as neurotransmitter receptors to modulate synaptic activity, pathological mGluR5 signaling has been implicated in a number of disease processes including Fragile X, amyotrophic lateral sclerosis, multiple sclerosis, Alzheimer's disease, Parkinson's disease, Huntington's disease, epilepsy, and drug addiction. The expression of mGluR5 in astrocytes has been shown to be increased in several acute and chronic neurodegenerative conditions, but little is known about the functional relevance of mGluR5 up-regulation in astrocytes following injury.

RESULTS: In the current study, we investigated primary mouse cortical astrocyte cell death in response to oxygen glucose deprivation (OGD) and found that OGD induced both necrotic and apoptotic cell death of astrocytes. OGD resulted in an increase in astrocytic mGluR5 protein expression, inositol phosphate formation and extracellular regulated kinase (ERK1/2) phosphorylation, but only inositol phosphate formation was blocked with the mGluR5 selective antagonist MPEP. Cortical astrocytes derived from mGluR5 knockout mice exhibited resistance to OGD-stimulated apoptosis, but a lack of mGluR5 expression did not confer protection against necrotic cell death. The antagonism of the inositol 1,4,5 trisphosphate receptor also reduced apoptotic cell death in wild-type astrocytes, but did not provide any additional protection to astrocytes derived from mGluR5 null mice. Moreover, the disruption of Homer protein interactions with mGluR5 also reduced astrocyte apoptosis.

CONCLUSION: Taken together these observations indicated that mGluR5 up-regulation contributed selectively to the apoptosis of astrocytes via the activation of phospholipase C and the release of calcium from intracellular stores as well as via the association with Homer proteins.

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Role of metabotropic glutamate receptor 5 signaling and homer in oxygen glucose deprivation-mediated astrocyte apoptosis

Abstract

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