Elsevier

Neuropharmacology

Volume 38, Issue 10, October 1999, Pages 1477-1484
Neuropharmacology

Short survey
Group-I metabotropic glutamate receptors: hypotheses to explain their dual role in neurotoxicity and neuroprotection

https://doi.org/10.1016/S0028-3908(99)00102-1Get rights and content

Abstract

The role of group-I metabotropic glutamate receptors (mGlu1 and 5) in neurodegeneration is still controversial. While antagonists of these receptors are consistently neuroprotective, agonists have been found to either amplify or attenuate excitotoxic neuronal death. At least three variables affect responses to agonists: (i) the presence of the NR2C subunit in the NMDA receptor complex; (ii) the existence of an activity-dependent functional switch of group-I mGlu receptors, similar to that described for the regulation of glutamate release; and (iii) the presence of astrocytes expressing mGlu5 receptors. Thus, a number of factors, including the heteromeric composition of NMDA receptors, the exposure time to drugs or to ambient glutamate, and the function of astrocytes clearing extracellular glutamate and producing neurotoxic or neuroprotective factors, must be taken into account when examining the role of group-I mGlu receptors in neurodegeneration/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

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