Astroglial Phosphoinositide Hydrolysis During Combined Glucose‐Oxygen Deprivation: Role of the Metabotropic Glutamate Receptor

Segeleon, Joseph E.; Lipscomb, Diane C.; Haun, Steven E.; Trapp, Victoria L.; Horrocks, Lloyd A.

doi:10.1046/j.1471-4159.1995.65031115.x

Cited by 10 publications

(6 citation statements)

References 39 publications

(57 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Indeed, ischemic conditions could result in glutamate release by astrocytes through a variety of mechanisms [35]. The observed increases in InsP formation following OGD are consistent with previous work demonstrating that OGD results in increased InsP formation, likely via a metabotropic glutamate receptor [36]. …”

Section: Discussionsupporting

confidence: 86%

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

et al. 2013

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionsupporting

confidence: 86%

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

et al. 2013

View full text Add to dashboard Cite

show abstract

“…1990; Jensen and Chiu 1990; Holtzclaw et al . 1995; Segeleon et al . 1995; Steinhauser and Gallo 1996; Ciccarelli et al .…”

mentioning

confidence: 99%

Functional metabotropic glutamate receptors are expressed in oligodendrocyte progenitor cells

Luyt

Váradi

Molnár

2003

Journal of Neurochemistry

View full text Add to dashboard Cite

We investigated the expression of metabotropic glutamate receptor (mGluR) isoforms in CG-4 rodent oligodendroglial progenitor cells (OPC) and rat brain oligodendrocytes. Our RT-PCR analysis detected mRNAs for mGluR3 and mGluR5 isoforms in OPCs. Although neurons express both mGluR5a and mGluR5b splice variants, only mGluR5a was identified in OPCs. Antibodies to mGluR2/3 and mGluR5 detected the corresponding receptor proteins in immunoblots of OPC membrane fractions. Furthermore, immunocytochemical analysis identified mGluR5 in oligodendrocyte marker O4-positive OPCs. The expression of mGluR5 was also demonstrated in oligodendrocyte marker (O4 and O1) positive cells in white matter of postnatal 4-and 7-day-old rat brain sections using immunofluorescent double labelling and confocal microscopy. The mGluR5 receptor function was assessed in CG-4OPCs with fura-2 microfluorometry. Application of the mGluR1/5 specific agonist (S)-3,5-dihydroxyphenylglycine (DHPG) induced calcium oscillations, which were inhibited by the selective mGluR5 antagonist 2-methyl-6-(phenylethynyl) pyridine hydrochloride (MPEP). The DHPG induced calcium oscillations required Ca 2+ release from intracellular stores. InOPCs the group II mGluR agonist (2S,2¢R,3¢R)-2-(2¢,3¢-dicarboxycyclopropyl)glycine (DCG-IV) decreased forskolin-stimulated cAMP synthesis, indicating the presence of functional mGluR3. The newly identified mGluR3 and mGluR5a may be involved in the differentiation of oligodendrocytes, myelination and the development of white matter damage. Glutamate is the major excitatory neurotransmitter in the CNS and its responses are mediated by ionotropic (iGluRs) and metabotropic (mGluRs) glutamate receptors. The iGluRs mediate fast synaptic transmission and the mGluRs are involved in a variety of modulatory events associated with neuronal activity. The iGluRs are multimeric, cation-specific ion channels that are classified into three families on the basis of their pharmacology, electrophysiology and sequence homology: namely the a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), kainate, and N-methyl-D-aspartate (NMDA) receptors (Dingledine et al. 1999). The mGluRs are G-protein coupled receptors, which mediate relatively slow responses to glutamate. There are eight mGluR genes (mGluR1-8) and these have been divided into three groups based on pharmacological, signal transduction and sequence similarities. Group I comprises mGluR1 and mGluR5, which are involved in the mobilization of intracellular calcium by stimulating phospholipase C and are activated by (S)-3,5-dihydroxyphenylglycine (DHPG). In group II, the mGluR2 and mGluR3 are typically linked to inhibition of adenylyl cyclase (AC) and react effectively with (2S,1¢S,2¢S)-2-(carboxycyclopropyl)glycine (DCG-IV). In group III, the mGluR4, mGluR6, mGluR7 and mGluR8 are linked to inhibition of cAMP formation by AC and respond effectively to L-2-amino-4-phosphonobutyrate (Conn and Pin 1997;Schoepp et al. 1999). Oligodendrocytes are responsible for axon myelination and they a...

show abstract

Section: Discussionmentioning

confidence: 99%

“…They also give information useful to clarify the role of mGluRI, including mGluR1, in brain pathology. In fact, the lowering of oxygen availability by N 2 treatment has been used not only in slices but also in cell cultures to experimentally reproduce brain hypoxia, and, when the medium lacks glucose, brain ischaemia (Segeleon et al 1995). Recent evidence has demonstrated that also mGluRs are involved in excitotoxicity (for a review see Nicoletti et al 1996) and that group I mGluRs participate in a variety of disorders such as pain, epilepsy, ischaemia and chronic neurodegenerative disease (for a review see Bordi and Ugolini 1999).…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Group I metabotropic glutamate receptors mediate the inhibition of phosphatidylserine synthesis in rat cerebellar slices: a possible role in physiology and pathology

Buratta¹,

Mambrini²,

Miniaci

et al. 2004

Journal of Neurochemistry

View full text Add to dashboard Cite

In cerebellar slices, the lowering of oxygen availability, obtained by bubbling N 2 in the medium, reduced the incorporation of radioactive serine into phosphatidylserine (PtdSer). CPCCOEt, an antagonist of metabotropic glutamate receptors type 1 (mGluR1) counteracted the effect, whereas antagonists of NMDA or AMPA receptors were ineffective. In oxygenated slices, agonists of Group I mGluRs, which include mGluR1, inhibited PtdSer synthesis. This effect was also counteracted by CPCCOEt. These findings indicate that glutamate inhibits PtdSer synthesis by acting on mGluR1. This could be important in relation to the known release of glutamate in hypoxia-ischaemia conditions. In cerebellar Purkinje cells, mGluR1 are involved in the generation of mGluR-EPSP evoked by parallel fibre stimulation. The administration of L-serine to cerebellar slices reduced in a dose-dependent manner the mGluR-EPSP evoked by parallel fibre stimulation. The effect was mostly due to the increased synthesis of PtdSer. Thus inhibition of PtdSer synthesis, mediated by mGluR1, may participate in the generation of mGluR-EPSP. Membrane phospholipids play relevant roles in cell functions, including response to external stimuli involving signal transduction mechanisms. Since the early demonstration that diacylglycerol (DAG) produced from phosphatidylinositol bisphosphate (PIP 2 ) acts as second messenger for the activation of protein kinase C (PKC), many reports have evidenced the complexity of this transduction pathway, which involves other membrane phospholipids. In fact, DAG originates not only from PIP2 and various lipid mediators modulate PKC activity (for a review see Nishizuka 1995). Membrane phospholipids are not only the source of PKC modulators but also the substrate for PKC-regulated enzymes that, in turn, produce lipid mediators and the complex network underlying signal transduction is characterized by strict cross-talk between the various lipid components. The dependence of all PKC isoforms on phosphatidylserine (PtdSer) focussed attention also on the eventual role of this phospholipid (for a review see Nishizuka 1995) and it has been suggested that DAG turns the enzyme on, whereas PtdSer influences the specificity toward different substrates (Newton and Johnson 1998).PtdSer and its metabolism enzymes have received great attention with respect to their role in brain function, which can be based not only on the influence on PKC activity but also the capability of this phospholipid to modulate the Abbreviations used: CPCCOEt, 7-(hydroxyimino)cyclopropa[b]chromen-1a-carboxylate ethyl ester; DAG, diacylglycerols; D-AP5, D-(-)-2-amino-5-phosphonopentanoic acid; EPSC, excitatory post-synaptic current; EPSP, excitatory post-synaptic potential; iGluR, ionotropic glutamate receptor; KRB, Krebs-Henseleit Ringer bicarbonate; NBQX, 2,3-dioxo-6-nitro-1,2,3,4-tetrahydrobenzo[f]quinoxaline-7-sulfonamide disodium salt; quisqualic acid, (L)-a-amino-3,5-dioxo-1,2,4-oxadiazolidine-2-propanoic acid; PLC, phospholipase C; PLD, phospholipase D; PtdS...

show abstract

Astroglial Phosphoinositide Hydrolysis During Combined Glucose‐Oxygen Deprivation: Role of the Metabotropic Glutamate Receptor

Cited by 10 publications

References 39 publications

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

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

Functional metabotropic glutamate receptors are expressed in oligodendrocyte progenitor cells

Group I metabotropic glutamate receptors mediate the inhibition of phosphatidylserine synthesis in rat cerebellar slices: a possible role in physiology and pathology

Contact Info

Product

Resources

About