Short surveyGroup-I metabotropic glutamate receptors: hypotheses to explain their dual role in neurotoxicity and neuroprotection
Introduction
In spite of the increasing availability of subtype-selective drugs, the role of group-I metabotropic glutamate (mGlu) receptors in neurode generation is still controversial. We wish to critically review the literature and offer possible explanations for conflicting data. mGlu1 and 5 receptors are coupled to polyphosphoinositide (PI) hydrolysis (reviewed by Nakanishi, 1994, Pin and Duvoisin, 1995), a metabolic process leading to mobilization of intracellular Ca2+ and activation of protein kinase C (PKC) as a result of inositol-1,4,5-trisphosphate (InsP3) and diacylglycerol (DAG) formation, respectively. Knowing that increases in free cytosolic Ca2+ and activation of PKC are components of the intracellular pathways leading to neuronal death (Choi, 1992), one can predict that mGlu1 and 5 receptors are potentially neurotoxic and their excessive activation may excerbate neuronal demise. However, this view is too simplistic and incorporates several pitfalls. Firstly, the assumption that native mGlu1 or 5 receptors are coupled to PI hydrolysis is only justified by the tissue response to a number of group-I mGlu receptor agonists. It is intriguing that selective mGlu1 receptor antagonists, such as 7-(hydroxyimino)cyclopropa[b] chromen-1a-carboxylate ethyl ester (CPCCOEt) or 4-carboxy-3-hydroxyphenylglycine fail to reduce excitatory amino acid-stimulated PI hydrolysis in brain slices (Casabona et al., 1997), whereas studies with selective mGlu5 receptor antagonists have not yet been performed. Secondly, the possibility that group-I mGlu receptors are coupled to other transduction pathways cannot be ignored. For example, studies on native or heterologous expression systems indicate that group-I mGlu receptors are negatively coupled to different types of K+ channels, and also couple to voltage sensitive Ca2+ channels (Ikeda et al., 1995; reviewed in Pin and Duvoisin, 1995). Thirdly, even focusing on PI hydrolysis, one should bear in mind that increases in cytosolic free Ca2+ may have not only detrimental but also protective effects. Ca2+ may reduce the activity of voltage- or ligand-gated ion channels by activating protein phosphatates; in addition, Ca2+ affects the anchorage of the NR2 subunit to cytoskeletal proteins, and may therefore induce changes in NMDA receptor function (see Chandler et al., 1998 and references therein). Fourthly, one cannot exclude that the currently available group-I mGlu receptor agonists, such as 3,5-dihydroxyphenylglycine (DHPG), 3-hydroxy phenylglycine (3HPG) or quisqualate, activate other as yet unidentified subtypes similar to mGlu1 and 5 receptors; for example, functional data suggest the existence of presynaptic group-I mGlu receptors (Gereau IV and Conn, 1995; see below), although neither m Glu1 nor mGlu5 receptors have been found in presynaptic terminals (Shigemoto et al., 1997, Baude et al., 1993). Fifthly, there is solid evidence for both neurotoxic and neuroprotective actions of group-I mGlu receptor agonists, and the reason for this discrepancy is unknown. After reviewing the literature, we will comment on some novel mechanisms that may enable us to understand why the use of group-I mGlu receptor agonists has generated conflicting results. Emphasis will be put on (i) the presence of the NR2C subunit in the NMDA receptor complex; (ii) the existence of a ‘functional switch’ between facilitatory and inhibitory mGlu receptors; and (iii) a role for glial mGlu5 receptors in neurodegeneration.
Section snippets
In vivo studies
Indirect evidence for a facilitatory role of group-I mGlu receptors in neurodegeneration was initially provided using the non-subtype selective agonist, (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid (1S,3R-ACPD). Local injections of 1S,3R-ACPD induce neurotoxic effects in the rat hippocampus or caudate nucleus (McDonald and Schoepp, 1992, Sacaan and Schoepp, 1992, McDonald et al., 1993), as well as in animal models of transient global ischemia (Henrich-Noack and Reymann, 1999). In adult
Permissive role for the NMDA receptor 2C subunit on neuroprotection mediated by group-I mGlu receptors
In cultured cerebellar granule cells group-I mGlu receptor agonists protect against excitotoxic damage and reduce the increase of cytosolic free Ca2+ that follows the activation of NMDA receptors. Both effects are mediated by PKC (Pizzi et al., 1996a). Pizzi et al. have hypothesized that the influence of group-I mGlu receptors on NMDA toxicity depends on the heteromeric composition of NMDA receptors. Functional NMDA receptors are formed by the assembly of the NR1 subunit with one or more NR2
Acknowledgements
Supported by the BIOMED grant VEBHH4-CT96-085
References (75)
- et al.
Rapid agonist mediated phosphorylation of the metabotropic glutamate receptor 1α by protein kinase C in permanently transfected BHK cells
FEBS Letters
(1995) - et al.
The 1a form of metabotropic glutamate receptor (mGluR 1a) is concentrated at extra and perisynaptic membrane of discrete subpopulations of neurons as detected by immunogold reaction in the rat
Neuron
(1993) - et al.
Activation of metabotropic glutamate receptors coupled to inositol phospholipid hydrolysis amplifies NMDA-induced neuronal degeneration in cultured cortical cells
Neuropharmacology
(1995) - et al.
Neuroprotective activity of the potent and selective mGlu1a metabotropic glutamate receptor antagonist, (+)-2-methyl-4-carboxyphenylglycine (LY367385): comparison with LY367366, a broader spectrum antagonist with equal affinity for mGlu1a and mGlu5 receptors.
Neuropharmacology
(1999) - et al.
The inibitory mGluR agonist, S-4-carboxy-3-hydroxy-phenylglycine selectively attenuates NMDA neurotoxicity and oxygen-glucose deprivation-induced neuronal death
Neuropharmacology
(1995) - et al.
G-protein activation by metabotropic glutamate receptors reduces spike frequency adaptation in neocortical neurons
Neuroscience
(1996) - et al.
Antisense oligodeoxynucleotides directed against mGluR5 glutamate receptor protect against malonic acid lesions in rat striatum
Neuropharmacology
(1996) - et al.
Ethanol tolerance and synaptic plasticity
Trends in Pharmacological Science
(1998) - et al.
2-Methyl-4-carboxyphenylglycine (LY367385) selectively antagonizes metabotropic glutamate mGluR1 receptors
Biorganic Medical Chemistry Letters
(1997) - et al.
Involvement of three GluR subunits in the formation of N-methyl-d-aspartate receptors mediating excitotoxicity in primary cultures of mouse cerebellar granule cells
Neuroscience
(1997)
In vitro neurotoxicity of excitatory amino acid analogues during cerebellar development
Neuroscience
(1S,3R)-ACPD, a metabotropic glutamate receptor agonist, enhances damage after global ischaemia
European Journal of Pharmacology
Functional switch from facilitation to inhibition in the presynaptic control of glutamate release by metabotropic glutamate receptors
Journal of Biological Chemistry
Heterologous expression of metabotropic gutamate receptor in adult rat sympathetic neurons: subtype specific coupling to ion channel
Neuron
Cloning of the cDNA for the human NMDA receptor NR2C subunit and its expression in the central nervous system and periphery
Brain Research, Molecular Brain Research
The effect of 2-amino-3-phosphonopropionic acid (AP-3) in the gerbil model of cerebral ischaemia
European Journal of Pharmacology
The metabotropic glutamate receptor agonist 1S,3R-ACPD selectively potentiates N-methyl-d-aspartate-induced brain injury
European Journal of Pharmacology
NMDA receptor-dependent excitotoxicity: the role of in tracellular Ca2+ release
Trends in Pharmacological Science
Developmental and regional expression in the rat brain and functional properties of four NMDA receptors
Neuron
Metabotropic glutamate receptors: synaptic transmission, modulation and plasticity
Neuron
Metabotropic glutamate receptors: a new target for the therapy of neurodegenerative disorders?
Trends in Neuroscience
(1S,3R)-ACPD protects synaptic transmission from hypoxia in hippocampal slices
Neuropharmacology
The metabotropic glutamate receptor antagonist (+)-(-methyl-4-carboxyphenylglycine protects hippocampal CA1 neurons of the rat from in vitro hypoxia/hypo glycemia
Neuropharmacology
The metabotropic glutamate receptors: structure and functions
Neuropharmacology
Blockade of the second messenger functions of the glutamate metabotropic receptor is associated with degenerative changes in the retina and brain of immature rodents
Neuropharmacology
Switch from facilitation to inhibition of excitatory synaptic transmission by the desensitization of group I mGluRs in the rat hippocampus
Neuron
Activation of hippocampal metabotropic excitatory amino acid receptors leads to seizures and neuronal damage
Neuroscience Letters
Metabotropic glutamate receptor modulation of cAMP accumulation in the neonatal rat hippocampus
Neuropharmacology
Protective effect of group I metabotropic glutamate receptor activation against hypoxic/hypoglycemic injury in rat hippocampal slices: timing and involvement of protein kinase C
Neuropharmacology
The metabotropic glutamate receptor 1 is not involved in the facilitation of glutamate release in cerebrocortical nerve terminals
Neuropharmacology
Alteration in NMDA receptor subunit mRNA expression in vulnerable and resistant regions of in vitro ischemic rat hippocampal slices
Neuroscience Letters
Prostaglandins stimulate calcium-dependent glutamate release in astrocytes
Nature
Expression and signaling of group I metabotropic glutamate receptors in astrocytes and microglia
Journal of Neurochemistry
The neuroprotective activity of group-II metabotropic glutamate receptors requires new protein synthesis and involves a glial–neuronal signaling
Journal of Neuroscience
Neuroprotection by glial metabotropic glutamate receptors is mediated by transforming growth factor-beta
Journal of Neuroscience
Seizures and neuronal damage induced in the rat by activation of group I metabotropic glutamate receptors with their selective agonist 3,5-dihydroxyphenylglycine
Journal of Neuroscience Research
Expression and coupling to polyphosphoinositide hydrolysis of group-I metabotropic glutamate receptors in early postnatal and adult rat brain
European Journal of Neuroscience
Cited by (158)
Glutamate receptor endocytosis and signaling in neurological conditions
2023, Progress in Molecular Biology and Translational ScienceKainic acid-induced status epilepticus decreases mGlu<inf>5</inf> receptor and phase-specifically downregulates Homer1b/c expression
2020, Brain ResearchCitation Excerpt :Increased mGlu5 receptor expression in TLE patients was suggested to contribute to neuronal hyperexcitability of the hippocampal network (Notenboom et al., 2006; Tang et al., 2001). Alternatively, the upregulated mGlu5 receptor might protect hippocampal neurons against over-excitation and neurotoxicity (Nicoletti et al., 1999). Despite excessive extracellular glutamate, mGlu5 receptor activation may desensitize glutamatergic neurotransmission through internalization of synaptic NMDA receptors and control glutamate release (Rodriguez-Moreno et al., 1998; Snyder et al., 2001).
Knockdown of RTN1-C attenuates traumatic neuronal injury through regulating intracellular Ca<sup>2+</sup> homeostasis
2018, Neurochemistry InternationalNeurotransmitter Receptors
2018, Comprehensive Toxicology: Third EditionExcitotoxicity
2018, Comprehensive Toxicology: Third Edition