Metabotropic glutamate receptors: From the workbench to the bedside

doi:10.1016/j.neuropharm.2010.10.022

Neuropharmacology

Volume 60, Issues 7–8, June 2011, Pages 1017-1041

In memory of Prof. Erminio Costa.

https://doi.org/10.1016/j.neuropharm.2010.10.022 Get rights and content

Abstract

Metabotropic glutamate (mGlu) receptors were discovered in the mid 1980s and originally described as glutamate receptors coupled to polyphosphoinositide hydrolysis. Almost 6500 articles have been published since then, and subtype-selective mGlu receptor ligands are now under clinical development for the treatment of a variety of disorders such as Fragile-X syndrome, schizophrenia, Parkinson’s disease and l-DOPA-induced dyskinesias, generalized anxiety disorder, chronic pain, and gastroesophageal reflux disorder. Prof. Erminio Costa was linked to the early times of the mGlu receptor history, when a few research groups challenged the general belief that glutamate could only activate ionotropic receptors and all metabolic responses to glutamate were secondary to calcium entry. This review moves from those nostalgic times to the most recent advances in the physiology and pharmacology of mGlu receptors, and highlights the role of individual mGlu receptor subtypes in the pathophysiology of human disorders.

This article is part of a Special Issue entitled ‘Trends in Neuropharmacology: In Memory of Erminio Costa’.

Section snippets

Historical background

The evidence that quisqualate and glutamate stimulated inositol phosphate formation in cultured striatal neurons (Sladeczek et al., 1985) offered the first demonstration that excitatory amino acids could activate receptors other than the classical ligand-gated ion channels (named NMDA, “quisqualate” and kainate receptors at that time). In the meantime, ibotenic acid, a heterocyclic amino acid naturally occurring in the mushrooms Amanita muscaria and Amanita pantherina, was found to stimulate

Structure and activation mechanism of mGluRs

Sequence analysis of most class CG-protein coupled receptors (GPCRs), including the 8 mGlu receptor subtypes, the Ca²⁺-sensing receptor, the taste T1R receptors, and the basic amino acid receptor GPCR6a, revealed that these receptors have a large extracellular domain made of a Venus Fly Trap (VFT) domain similar to the periplasmic bacterial leucine/isoleucine/valine binding protein (LIVBP) linked to the first TM domain via a cysteine-rich domain (CRD) containing 9 highly conserved cysteine

mGlu1 receptor

Gene name: GRM1 (human); Grm1 (rat, mouse). Accession numbers: NP_000829 (human); NP_058707 (rat); NP_058672 (mouse). Chromosomal location: 6q24 (human); 1p13 (rat); 10A2 (mouse) (Masu et al., 1991, Kuramoto et al., 1994, Desai et al., 1995, Stephan et al., 1996).

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Allosteric modulation of G protein-coupled receptors as a novel therapeutic strategy in neuropathic pain
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Neuropathic pain is a debilitating pathological condition that presents significant therapeutic challenges in clinical practice. Unfortunately, current pharmacological treatments for neuropathic pain lack clinical efficacy and often lead to harmful adverse reactions. As G protein-coupled receptors (GPCRs) are widely distributed throughout the body, including the pain transmission pathway and descending inhibition pathway, the development of novel neuropathic pain treatments based on GPCRs allosteric modulation theory is gaining momentum. Extensive research has shown that allosteric modulators targeting GPCRs on the pain pathway can effectively alleviate symptoms of neuropathic pain while reducing or eliminating adverse effects. This review aims to provide a comprehensive summary of the progress made in GPCRs allosteric modulators in the treatment of neuropathic pain, and discuss the potential benefits and adverse factors of this treatment. We will also concentrate on the development of biased agonists of GPCRs, and based on important examples of biased agonist development in recent years, we will describe universal strategies for designing structure-based biased agonists. It is foreseeable that, with the continuous improvement of GPCRs allosteric modulation and biased agonist theory, effective GPCRs allosteric drugs will eventually be available for the treatment of neuropathic pain with acceptable safety.
Amyloid-β<inf>1-42</inf> oligomers enhance mGlu<inf>5</inf>R-dependent synaptic weakening via NMDAR activation and complement C5aR1 signaling
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Synaptic weakening and loss are well-correlated with the pathology of Alzheimer’s disease (AD). Oligomeric amyloid beta (oAβ) is considered a major synaptotoxic trigger for AD. Recent studies have implicated hyperactivation of the complement cascade as the driving force for loss of synapses caused by oAβ. However, the initial synaptic cues that trigger pathological complement activity remain elusive. Here, we examined a form of synaptic long-term depression (LTD) mediated by metabotropic glutamate receptors (mGluRs) that is disrupted in rodent models of AD. Exogenous application of oAβ (1–42) to mouse hippocampal slices enhanced the magnitude of mGlu subtype 5 receptor (mGlu₅R)-dependent LTD. We found that the enhanced synaptic weakening occurred via both N-methyl-D-aspartate receptors (NMDARs) and complement C5aR1 signaling. Our findings reveal a mechanistic interaction between mGlu₅R, NMDARs, and the complement system in aberrant synaptic weakening induced by oAβ, which could represent an early trigger of synaptic loss and degeneration in AD.
Presynaptic glutamate receptors in nociception
2023, Pharmacology and Therapeutics
Chronic pain is a frequent, distressing and poorly understood health problem. Plasticity of synaptic transmission in the nociceptive pathways after inflammation or injury is assumed to be an important cellular basis for chronic, pathological pain. Glutamate serves as the main excitatory neurotransmitter at key synapses in the somatosensory nociceptive pathways, in which it acts on both ionotropic and metabotropic glutamate receptors. Although conventionally postsynaptic, compelling anatomical and physiological evidence demonstrates the presence of presynaptic glutamate receptors in the nociceptive pathways. Presynaptic glutamate receptors play crucial roles in nociceptive synaptic transmission and plasticity. They modulate presynaptic neurotransmitter release and synaptic plasticity, which in turn regulates pain sensitization. In this review, we summarize the latest understanding of the expression of presynaptic glutamate receptors in the nociceptive pathways, and how they contribute to nociceptive information processing and pain hypersensitivity associated with inflammation / injury. We uncover the cellular and molecular mechanisms of presynaptic glutamate receptors in shaping synaptic transmission and plasticity to mediate pain chronicity, which may provide therapeutic approaches for treatment of chronic pain.
Blunted type-5 metabotropic glutamate receptor-mediated polyphosphoinositide hydrolysis in two mouse models of monogenic autism
2023, Neuropharmacology
The involvement of the mGlu5 receptors in the pathophysiology of several forms of monogenic autism has been supported by numerous studies following the seminal observation that mGlu5 receptor-dependent long-term depression was enhanced in the hippocampus of mice modeling the fragile-X syndrome (FXS). Surprisingly, there are no studies examining the canonical signal transduction pathway activated by mGlu5 receptors (i.e. polyphosphoinositide – PI – hydrolysis) in mouse models of autism. We have developed a method for in vivo assessment of PI hydrolysis based on systemic injection of lithium chloride followed by treatment with the selective mGlu5 receptor PAM, VU0360172, and measurement of endogenous inositolmonophosphate (InsP) in brain tissue. Here, we report that mGlu5 receptor-mediated PI hydrolysis was blunted in the cerebral cortex, hippocampus, and corpus striatum of Ube3a^m−/p+ mice modeling Angelman syndrome (AS), and in the cerebral cortex and hippocampus of Fmr1 knockout mice modeling FXS. In vivo mGlu5 receptor-mediated stimulation of Akt on threonine 308 was also blunted in the hippocampus of FXS mice. These changes were associated with a significant increase in cortical and striatal Homer1 levels and striatal mGlu5 receptor and Gαq levels in AS mice, and with a reduction in cortical mGlu5 receptor and hippocampal Gαq levels, and an increase in cortical phospholipase-Cβ and hippocampal Homer1 levels in FXS mice.
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GPCR interactions involving metabotropic glutamate receptors and their relevance to the pathophysiology and treatment of CNS disorders
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This article is part of the Special Issue on “The receptor-receptor interaction as a new target for therapy”.

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Metabotropic glutamate receptors: From the workbench to the bedside

Abstract

Section snippets

Historical background

Structure and activation mechanism of mGluRs

mGlu1 receptor

J. Biol. Chem.

Brain Res.

Cell

Neuropharmacology

Neuroscience

Brain Res. Bull.

Behav. Brain Res.

Exp. Neurol.

Cell

Neuropharmacology

Neurosci. Lett.

Neuropharmacology

Neuron

Neuropharmacology

J. Biol. Chem.

Neuroscience

Schizophr. Res.

Neurosci. Lett.

Neuropharmacology

Neuropharmacology

Neuropharmacology

Neuropharmacology

Neuron

Pharmacol. Biochem. Behav.

Neuropharmacology

Brain Res.

Trends Neurosci.

Neuropharmacology

Am. J. Clin. Nutr.

Trends Pharmacol. Sci.

Neuropharmacology

Biol. Psychiatry

Trends Pharmacol. Sci.

Biol. Psychiatry

Metaplasticity: tuning synapses and networks for plasticity

Nat. Rev. Neurosci.

Pharmacological stimulation of group II metabotropic glutamate receptors reduces cocaine self-administration and cocaine-induced reinstatement of drug seeking in squirrel monkeys

J. Pharmacol. Exp. Ther.

IP3 receptor sensitization during in vivo amphetamine experience enhances NMDA receptor plasticity in dopamine neurons of the ventral tegmental area

J. Neurosci.

Pharmacological blockade of group II metabotropic glutamate receptors reduces the growth of glioma cells in vivo

Neuro Oncol.

Upregulation of metabotropic glutamate receptor subtype mGluR3 and mGluR5 in reactive astrocytes in a rat model of mesial temporal lobe epilepsy

Eur. J. Neurosci.

Expression and cell distribution of group I and group II metabotropic glutamate receptor subtypes in taylor-type focal cortical dysplasia

Epilepsia

Activation of type 5 metabotropic glutamate receptors enhances NMDA responses in mice cortical wedges

Br. J. Pharmacol.

Activation of metabotropic glutamate receptor 5 has direct excitatory effects and potentiates NMDA receptor currents in neurons of the subthalamic nucleus

J. Neurosci.

Metabotropic glutamate receptor mGluR5 in astrocytes: pharmacological properties and agonist regulation

J. Neurochem.

The effect of the mGlu5 receptor antagonist MPEP in rodent tests of anxiety and cognition: a comparison

Psychopharmacology (Berl.)

Assignment of the human metabotropic glutamate receptor gene GRM4 to chromosome 6 band p21.3 by radiation hybrid mapping

Cytogenet. Cell. Genet.

Assignment of the human metabotropic glutamate receptor gene GRM7 to chromosome 3p26.1 → p25.2 by radiation hybrid mapping

Cytogenet. Cell. Genet.

Frequency detection and temporally dispersed synaptic signal association through a metabotropic glutamate receptor pathway

Nature

Selective blockade of mGlu5 metabotropic glutamate receptors is protective against methamphetamine neurotoxicity

J. Neurosci.

Endogenous activation of mGlu5 metabotropic glutamate receptors contributes to the development of nigro-striatal damage induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in mice

J. Neurosci.

Activation of mGlu3 receptors stimulates the production of GDNF in striatal neurons

PLoS One