Chapter III Metabotropic glutamate receptors — immunocytochemical and in situ hybridization analyses

doi:10.1016/S0924-8196(00)80044-5

Handbook of Chemical Neuroanatomy

Volume 18, 2000, Pages 63-98

https://doi.org/10.1016/S0924-8196(00)80044-5 Get rights and content

Publisher Summary

This chapter focuses on metabotropic glutamate receptors (mGluRs). These receptors are linked to several intracellular signal transduction mechanisms via G-protein and are implicated in diverse functions of the mammalian central nervous system (CNS). These functions include mediation of slow excitatory and inhibitory responses; regulation of calcium channels, potassium channels, and non-selective cation channels; inhibition and facilitation of transmitter release; induction of long-term potentiation and long-term depression; and regulation of neuronal development. Functional diversity of the metabotropic glutamate receptor is reflected in molecular diversity of receptor subtypes. The sites of action of mGluRs are widely found throughout different membrane compartments of neuronal and glial cells. The chapter reviews the differential subcellular localization of metabotropic glutamate receptors in relation to transmitter release sites. Patterns of subcellular localization of mGluRs are different among three subgroups: group I and III mGluRs are mainly localized to somatodendritic and axonal domains of neurons, respectively, while group II mGluRs are extensively localized to both domains as well as to glial cell processes.

References (159)

AbeT et al.
Molecular characterization of a novel metabotropic glutamate receptor mGluR5 coupled to inositol phosphate/Ca²⁺ signal transduction
J Biol Chem
(1992)
AkazawaC et al.
Expression of mRNAs of l-AP4-sensitive metabotropic glutamate receptors (mGluR4, mGluR6, mGluR7) in the rat retina
Neurosci Lett
(1994)
AnwylR
Metabotropic glutamate receptors: electrophysiological properties and role in plasticity
Brain Res Rev
(1999)
BabaA et al.
Inhibitory glutamate response on cyclic AMP formation in cultured astrocytes
Neurosci Lett
(1993)
BatchelorAM et al.
Synaptic activation of metabotropic glutamate receptors in the parallel fibre-Purkinje cell pathway in rat cerebellar slices
Neuroscience
(1994)
BaudeA et al.
The metabotropic glutamate receptor (mGluR1a) is concentrated at perisynaptic membrane of neuronal subpopulations as detected by immunogold reaction
Neuron
(1993)
BertheleA et al.
Differential expression of rat and human type 1 metabotropic glutamate receptor splice variant messenger RNAs
Neuroscience
(1998)
BertheleA et al.
Distribution and developmental changes in metabotropic glutamate receptor messenger RNA expression in the rat lumber spinal cord
Dev Brain Res
(1999)
BortolottoZA et al.
Characterisation of LTP induced by the activation of glutamate metabotropic receptors in area CA1 of the hippocampus
Neuropharmacology
(1993)
FlorPJ et al.
A novel splice variant of a metabotropic glutamate receptor, human mGluR7b
Neuropharmacology
(1997)

FotuhiM et al.

Differential expression of metabotropic glutamate receptors in the hippocampus and entorhinal cortex of the rat

Mol Brain Res

(1994)

FrenguelliBG et al.

Metabotropic glutamate receptors and calcium signalling in dendrites of hippocampal CA1 neurones

Neuropharmacology

(1993)

GuthmannA et al.

Distribution of metabotropic glutamate receptors in the parabrachial and Kölliker-Fuse nuclei of the rat

Neuroscience

(1999)

HampsonDR et al.

Characterization of two alternatively spliced forms of a metabotropic glutamate receptor in the central nervous system of the rat

Neuroscience

(1994)

KanoM et al.

Persistent multiple climbing fiber innervation of cerebellar Purkinje cells in mice lacking mGluR1

Neuron

(1997)

KernerJA et al.

Expression of group one metabotropic glutamate receptor subunit mRNAs in neurochemically identified neurons in the rat neostriatum, neocortex, and hippocampus

Mol Brain Res

(1997)

KinoshitaA et al.

Presynaptic localization of a metabotropic, glutamate receptor, mGluR8, in the rhinencephalic areas: a light and electron microscope study in the rat

Neurosci Lett

(1996)

KinoshitaA et al.

Presynaptic localization of a metabotropic glutamate receptor, mGluR4a, in the cerebellar cortex: a light and electron microscope study in the rat

Neurosci Lett

(1996)

KinzieJM et al.

Distribution of metabotropic glutamate receptor 7 messenger RNA in the developing and adult rat brain

Neuroscience

(1995)

LesterRAJ et al.

Quisqualate receptor-mediated depression of calcium currents in hippocampal neurons

Neuron

(1990)

LindenDJ et al.

A long-term depression of AMPA currents in cultured cerebellar Purkinje neurons

Neuron

(1991)

LujánR et al.

Differential plasma membrane distribution of metabotropic glutamate receptors mGluR1a, mGluR2 and mGluR5, relative to neurotransmitter release sites

J Chem Neuroanat

(1997)

MakoffA et al.

Molecular characterization and localization of human metabotropic glutamate receptor type 4

Mol Brain Res

(1996)

MakoffA et al.

Molecular characterization and localization of human metabotropic glutamate receptor type 3

Mol Brain Res

(1996)

MartinLJ et al.

Cellular localization of a metabotropic glutamate receptor in rat brain

Neuron

(1992)

MaryS et al.

The rat mGlu1d receptor splice variant shares functional properties with the other short isoforms of mGlu1 receptor

Eur J Pharmacol

(1997)

MasuM et al.

Specific deficit of the ON response in visual transmission by targeted disruption of the mGluR6 gene

Cell

(1995)

MateosJM et al.

Clustering of the group III metabotropic glutamate receptor 4a at parallel fiber synaptic terminals in the rat cerebellar molecular layer

Neurosci Res

(1999)

MineffE et al.

Metabotropic glutamate receptors 2 and 3 expressed by astrocytes in rat ventrobasal thalamus

Neurosci Lett

(1999)

NakajimaY et al.

Molecular characterization of a novel retinal metabotropic glutamate receptor mGluR6 with a high agonist selectivity for l-2-amino-4-phosphonobutyrate

J Biol Chem

(1993)

NekiA et al.

Pre- and postsynaptic localization of a metabotropic glutamate receptor, mGluR2, in the rat brain: an immunohistochemical study with a monoclonal antibody

Neurosci Lett

(1996)

NekiA et al.

Metabotropic glutamate receptors mGluR2 and mGluR5 are expressed in two non-overlapping populations of Golgi cells in the rat cerebellum

Neuroscience

(1996)

NomuraA et al.

Developmentally regulated postsynaptic localization of a metabotropic glutamate receptor in rat rod bipolar cells

Cell

(1994)

NusserZ et al.

Subsynaptic segregation of metabotropic and ionotropic glutamate receptors as revealed by immunogold localization

Neuroscience

(1994)

OhishiH et al.

Distribution of the messenger RNA for a metabotropic glutamate receptor, mGluR2, in the central nervous system of the rat

Neuroscience

(1993)

OhishiH et al.

Immunohistochemical localization of metabotropic glutamate receptors, mGluR2 and mGluR3, in rat cerebellar cortes

Neuron

(1994)

BaskysA et al.

Agonists at metabotropic glutamate receptors presynaptically inhibit EPSCs in neonatal rat hippocampus

J Physiol

(1991)

BolshakovVY et al.

Postsynaptic induction and presynaptic expression of hippocampal long-term depression

Science

(1994)

BoxallSJ et al.

Enhanced expression of metabotropic glutamate receptor 3 messenger RNA in the rat spinal cord during ultraviolet irradiation induced peripheral inflammation

Neuroscience

(1998)

BradleySR et al.

Immunocytochemical localization of group III metabotropic glutamate receptors in the hippocampus with subtype-specific antibodies

J Neurosci

(1996)

BradleySR et al.

Distribution and developmental regulation of metabotropic glutamate receptor 7a in rat brain

J Neurochem

(1998)

BradleySR et al.

Immunohistochemical localization of subtype 4a metabotropic glutamate receptors in the rat and mouse basal ganglia

J Comp Neurol

(1999)

BrandstätterJH et al.

Compartmental localization of a metabotropic glutamate receptor (mGluR7): two different active sites at a retinal synapse

J Neurosci

(1996)

CaiW et al.

Localization of metabotropic glutamate receptors mGluR1a and mGluR2/3 in the cat retina

J Comp Neurol

(1999)

CharpakS et al.

Potassium conductances in hippocampal neurons blocked by excitatory amino-acid transmitters

Nature

(1990)

ChavisP et al.

The metabotropic glutamate receptor types 2/3 inhibit l-type calcium channels via a pertussis toxin-sensitive G-protein in cultured cerebellar granule cells

J Neurosci

(1994)

ChoiS et al.

Metabotropic glutamate receptor modulation of voltage-gated Ca²⁺ channels involves multiple receptor subtypes in cortical neurons

J Neurosci

(1996)

CongarP et al.

A long-lasting calcium-activated nonselective cationic current is generated by synaptic stimulation or exogenous activation of group I metabotropic glutamate receptors in CA1 pyramidal neurons

J Neurosci

(1997)

ConnJ et al.

Pharmacology and functions of metabotropic glutamate receptors

Annu Rev Pharmacol Toxicol

(1997)

ConquetF et al.

Motor deficit and impairment of synaptic plasticity in mice lacking mGluR1

Nature

(1994)

Cited by (105)

Symmetric signal transduction and negative allosteric modulation of heterodimeric mGlu1/5 receptors
2021, Neuropharmacology
For a long time metabotropic glutamate receptors (mGluRs) were thought to regulate neuronal functions as obligatory homodimers. Recent reports, however, indicate the existence of heterodimers between group-II and –III mGluRs in the brain, which differ from the homodimers in their signal transduction and sensitivity to negative allosteric modulators (NAMs). Whether the group-I mGluRs, mGlu1 and mGlu5, form functional heterodimers in the brain is still a matter of debate. We now show that mGlu1 and mGlu5 co-purify from brain membranes and hippocampal tissue and co-localize in cultured hippocampal neurons. Complementation assays with mutants deficient in agonist-binding or G protein-coupling reveal that mGlu1/5 heterodimers are functional in heterologous cells and transfected cultured hippocampal neurons. In contrast to heterodimers between group-II and –III mGluRs, mGlu1/5 receptors exhibit a symmetric signal transduction, with both protomers activating G proteins to a similar extent. NAMs of either protomer in mGlu1/5 receptors partially inhibit signaling, showing that both protomers need to be able to reach an active conformation for full receptor activity. Complete heterodimer inhibition is observed when both protomers are locked in their inactive state by a NAM. In summary, our data show that mGlu1/5 heterodimers exhibit a symmetric signal transduction and thus intermediate signaling efficacy and kinetic properties. Our data support the existence of mGlu1/5 heterodimers in neurons and highlight differences in the signaling transduction of heterodimeric mGluRs that influence allosteric modulation.
Defining the Homo- and Heterodimerization Propensities of Metabotropic Glutamate Receptors
2020, Cell Reports
The eight metabotropic glutamate receptors (mGluRs) serve critical modulatory roles throughout the nervous system. The molecular diversity of mGluRs is thought to be further expanded by the formation of heterodimers, but the co-expression of mGluR subtypes at the cellular level and the relative propensities of heterodimer formation are not well known. Here, we analyze single-cell RNA sequencing data and find that cortical pyramidal cells express multiple mGluR subtypes with distinct profiles for different receptor combinations. We then develop quantitative, fluorescence-based assays to define the relative homo- and heterodimer propensities across group-I, -II, and -III mGluRs. We find a strong preference for heterodimerization in a number of cases, including mGluR2 with mGluR3, which we confirm in frontal cortex using in situ RNA hybridization and co-immunoprecipitation. Together, our findings support the biological relevance of mGluR heterodimerization and highlight the complex landscape of mGluR populations in the brain.
Site selective activation of lateral hypothalamic mGluR1 and R5 receptors elicits feeding in rats
2015, Physiology and Behavior
Recent findings from our lab indicate that metabotropic glutamate receptor (mGluR) activation elicits eating, and the goal of the current study was to specify whether the lateral hypothalamus (LH) is the actual brain site mediating this effect. To examine this issue we injected the selective mGluR group I agonist (S)-3,5-dihydroxyphenylglycine (DHPG) unilaterally into the LH and surrounding regions (n = 5–8 subjects/brain site) of satiated adult male Sprague–Dawley rats and measured elicited feeding. We determined that 1.0 nmol elicited food intake only within the LH. Increasing the dose to 10 or 25 nmol produced a more sustained effect in the LH, and also elicited eating in several other brain sites. These results, demonstrating that the LH mediates the eating elicited by low doses of DHPG, suggest that the LH may contain mGluR whose activation can produce eating behavior.
Metabotropic glutamate receptor 5 as drug target for Fragile X syndrome
2015, Current Opinion in Pharmacology
Fragile X syndrome (FXS) is the most common monogenic form of inherited mental retardation caused by a trinucleotid repeat expansion and transcriptional shutdown of the FMR1 gene. FXS patients present a complex and often severe neuropsychiatric phenotype yet have mild somatic symptoms, normal life expectancies, and no indications of neurodegeneration. The therapeutic potential of mGlu5 inhibitors was proposed in the ‘mGluR theory of FXS’ based on early insights into the molecular pathophysiology of FXS. Studies in Fragile X mental retardation 1 (Fmr1) knock-out mice, a widely used disease model, demonstrated that mGlu5 inhibitors can correct a broad range of disease-related phenotypes. Recent clinical trials, however, with two different mGlu5 inhibitors (basimglurant and mavoglurant) showed no therapeutic benefit in FXS patients for reasons as yet unclear.
The metabotropic glutamate receptors: Potential drug targets for the treatment of anxiety disorders?
2014, European Journal of Pharmacology
Anxiety-related disorders are a common public health issue. Several lines of evidence suggest that altered glutamatergic neurotransmission underlies anxiety. Thus, novel molecules targeting glutamatergic neurotransmission, such as ligands of the metabotropic glutamate receptors (mGlurs) might be promising candidates for the treatment of anxiety disorders. To date, several ligands selective for each mGlu receptor (mGlur) have been synthesized, and pharmacological significances of these compounds have been demonstrated mainly in animal models. Here we critically review advances in research of these emerging molecular targets for the treatment of anxiety, discuss their advantages over currently used anxiolytics as well as remaining challenges.
Involvement of Glutamate in Learning and Memory
2013, Identification of Neural Markers Accompanying Memory
Since its discovery in the early 1950s, glutamate has been involved in fundamental functions, including neuronal plasticity, neurotoxicity, development, learning and memory. Describing our current knowledge of glutamate role in learning and memory processes would be impossible in few pages. Therefore, the aim of this chapter is to provide a brief overview of findings available to date, summarizing the main characteristic of glutamate receptors and their involvement in learning and memory. Moreover, we briefly describe the involvement of glutamate in hippocampal formation and, in particular, its role in learning and memory, including addiction as the persistence of maladaptive memory, and nervous diseases.

View all citing articles on Scopus

View full text

Chapter III Metabotropic glutamate receptors — immunocytochemical and in situ hybridization analyses

Publisher Summary

J Biol Chem

Neurosci Lett

Brain Res Rev

Neurosci Lett

Neuroscience

Neuron

Neuroscience

Dev Brain Res

Neuropharmacology

Neuropharmacology

Mol Brain Res

Neuropharmacology

Neuroscience

Neuroscience

Neuron

Mol Brain Res

Neurosci Lett

Neurosci Lett

Neuroscience

Neuron

Neuron

J Chem Neuroanat

Mol Brain Res

Mol Brain Res

Neuron

Eur J Pharmacol

Cell

Neurosci Res

Neurosci Lett

J Biol Chem

Neurosci Lett

Neuroscience

Cell

Neuroscience

Neuroscience

Neuron

Agonists at metabotropic glutamate receptors presynaptically inhibit EPSCs in neonatal rat hippocampus

J Physiol

Postsynaptic induction and presynaptic expression of hippocampal long-term depression

Science

Enhanced expression of metabotropic glutamate receptor 3 messenger RNA in the rat spinal cord during ultraviolet irradiation induced peripheral inflammation

Neuroscience

Immunocytochemical localization of group III metabotropic glutamate receptors in the hippocampus with subtype-specific antibodies

J Neurosci

Distribution and developmental regulation of metabotropic glutamate receptor 7a in rat brain

J Neurochem

Immunohistochemical localization of subtype 4a metabotropic glutamate receptors in the rat and mouse basal ganglia

J Comp Neurol

Compartmental localization of a metabotropic glutamate receptor (mGluR7): two different active sites at a retinal synapse

J Neurosci

Localization of metabotropic glutamate receptors mGluR1a and mGluR2/3 in the cat retina

J Comp Neurol

Potassium conductances in hippocampal neurons blocked by excitatory amino-acid transmitters

Nature

The metabotropic glutamate receptor types 2/3 inhibit l-type calcium channels via a pertussis toxin-sensitive G-protein in cultured cerebellar granule cells

J Neurosci

Metabotropic glutamate receptor modulation of voltage-gated Ca2+ channels involves multiple receptor subtypes in cortical neurons

J Neurosci

A long-lasting calcium-activated nonselective cationic current is generated by synaptic stimulation or exogenous activation of group I metabotropic glutamate receptors in CA1 pyramidal neurons

J Neurosci

Pharmacology and functions of metabotropic glutamate receptors

Annu Rev Pharmacol Toxicol

Motor deficit and impairment of synaptic plasticity in mice lacking mGluR1

Nature

Metabotropic glutamate receptor modulation of voltage-gated Ca²⁺ channels involves multiple receptor subtypes in cortical neurons