Abstract
BackgroundGroup 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.ResultsIn 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.ConclusionTaken 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.
Highlights
Group I metabotropic glutamate receptors are coupled via Gαq/11 to the activation of phospholipase Cβ, which hydrolyzes membrane phospholipids to form inositol 1,4,5 trisphosphate and diacylglycerol
oxygen glucose deprivation (OGD) induces both necrotic and apoptotic cell death of cortical asrtocytes To assess the effects of OGD on cortical astrocyte cell death, primary CD1 mouse cortical astrocytic cultures were subjected to an in vitro model of OGD to mimic ischemia for periods varying from 0 to 24 h followed by a 24 h reperfusion period
The increase in mGluR5a expression was not correlated with an increase in mGluR5a mRNA expression as determined by RT-PCR (Figure 2C) suggested that either mGluR5 turnover or mGluR5 protein translation was altered as a consequence of OGD
Summary
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. 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. Several neurotransmitter receptors are expressed in astrocytes including the G protein-coupled receptors (GPCRs) for the excitatory neurotransmitter glutamate. The metabotropic glutamate receptors (mGluRs) comprise the family C of GPCRs, which are characterized by sequence similarities in their seven transmembrane spanning helical domains and large extracellular aminoterminal venus fly trap domain [1,2,3]. Pharmacological and biochemical experiments have shown that mGluR5 is the predominant group I mGluR subtype expressed in cultures of brain astrocytes [5,6] mGluR1 is expressed in astrocytes in the spinal cord [7]
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