mGluR5 Protein

📖 Wiki Page

protein866 wordssynced 2026-04-02

<table class="infobox infobox-protein">
<tr>
<th class="infobox-header" colspan="2">mGluR5 Protein — Glutamate Metabotropic Receptor 5</th>
</tr>
<tr>
<td class="label">Protein Name</td>
<td>Metabotropic Glutamate Receptor 5</td>
</tr>
<tr>
<td class="label">Gene</td>
<td>GRM5</td>
</tr>
<tr>
<td class="label">UniProt ID</td>
<td>P41594</td>
</tr>
<tr>
<td class="label">PDB ID</td>
<td>6N51, 7LD7</td>
</tr>
<tr>
<td class="label">Molecular Weight</td>
<td>~143 kDa (1211 aa)</td>
</tr>
<tr>
<td class="label">Subcellular Localization</td>
<td>Postsynaptic density, [dendritic spines](/cell-types/dendritic-spines)</td>
</tr>
<tr>
<td class="label">Protein Family</td>
<td>Class C GPCR, mGluR family</td>
</tr>
<tr>
<td class="label">Drug</td>
<td>Mechanism</td>
</tr>
<tr>
<td class="label">CTEP</td>
<td>mGluR5 NAM</td>
</tr>
<tr>
<td class="label">Mavoglurant</td>
<td>mGluR5 NAM</td>
</tr>
<tr>
<td class="label">Basimglurant</td>
<td>mGluR5 NAM</td>
</tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/ms" style="color:#ef9a9a">Ms</a>, <a href="/wiki/schizophrenia" style="color:#ef9a9a">Schizophrenia</a></td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">6 edges</a></td>
</tr>
</table>

Introduction

...

mGluR5 Protein

Introduction

Mglur5 Protein — Glutamate Metabotropic Receptor 5 is an important component in the neurobiology of neurodegenerative diseases. This page provides detailed information about its structure, function, and role in disease processes.

Overview

mGluR5 (Metabotropic Glutamate Receptor 5) is a Group I metabotropic glutamate receptor that plays crucial roles in synaptic plasticity, learning, and memory, and is a functional receptor for [amyloid-beta](/proteins/amyloid-beta) oligomers in Alzheimer's disease. [@bear2004]

Protein Information

Structure

mGluR5 has the characteristic Class C GPCR architecture:

Large VFT Domain: Binds glutamate and related ligands
Cysteine-Rich Domain: Links extracellular and transmembrane domains
7-TM Domain: Seven transmembrane helices (TM1-TM7)
C-terminal Tail: Long intracellular tail with multiple interaction motifs

Normal Function

Calcium Signaling

Activates phospholipase Cβ (PLCβ)
Increases IP3 and DAG production
Releases calcium from intracellular stores
Activates PKC

Synaptic Plasticity

Critical for both [LTP](/mechanisms/long-term-potentiation) and LTD induction
Modulates [NMDA](/entities/nmda-receptor) receptor function
Regulates AMPA receptor trafficking

Learning and Memory

Essential for hippocampal-dependent learning
Involved in extinction learning
Regulates gene expression via MAPK/mTOR

Role in Disease

Alzheimer's Disease

Functional receptor for Aβ oligomers: Links amyloid pathology to synaptic dysfunction
Early dysregulation in AD pathogenesis
mGluR5 antagonists being investigated

Parkinson's Disease

Modulates dopaminergic signaling
mGluR5 antagonists reduce dyskinesias

Fragile X Syndrome

mGluR5 is overactive
mGluR5 NAMs in clinical trials

Depression and Anxiety

mGluR5 antagonists have anxiolytic effects

Therapeutic Targeting

Key Publications

Conn PJ, et al. (2009). Pharmacology and functions of metabotropic glutamate receptors. Annu Rev Pharmacol Toxicol. PMID: 18928405(https://pubmed.ncbi.nlm.nih.gov/18928405/)

Huber KM, et al. (2002). Altered mGluR5-dependent signaling in a mouse model of Fragile X. Nat Neurosci. PMID: 12368913(https://pubmed.ncbi.nlm.nih.gov/12368913/)

Renner M, et al. (2010). [Abeta](/proteins/amyloid-beta) oligomers act as a pathological signal in the brain. Neurodegener Dis. PMID: 20451513(https://pubmed.ncbi.nlm.nih.gov/20451513/)

Expression Pattern

mGluR5 shows region-specific expression:

Basal ganglia: High expression in striatum and nucleus accumbens
[Hippocampus](/brain-regions/hippocampus): CA1-CA3 pyramidal cells, dentate gyrus
[Cortex](/brain-regions/cortex): Layer V pyramidal [neurons](/entities/neurons)
Thalamus: Relay nuclei
Olfactory bulb: Mitral cells

Not expressed in cerebellum (unlike mGluR1).

Signaling Mechanisms

Group I mGluR Signaling

Gq coupling: Activates PLCβ → DAG/IP3 → Ca²⁺ release
MAPK pathway:ERK1/2 activation
[mTOR](/entities/mtor) pathway: Protein synthesis regulation
Ion channel modulation: Inhibition of K⁺ channels

Synaptic Localization

Predominantly postsynaptic
Adjacent to NMDA receptors
Involved in LTD and [LTP](/mechanisms/long-term-potentiation)

Role in Neurodegeneration

Alzheimer's Disease

mGluR5 is an Aβ receptor
Aβ-mGluR5 complex triggers synaptic dysfunction
Negative allosteric modulators: Neuroprotective
Cognitive deficits in mGluR5 knockout

Parkinson's Disease

Overactive in basal ganglia
Contributes to dyskinesias
mGluR5 antagonists: Anti-parkinsonian effects

Fragile X Syndrome

mGluR5 hypothesis: Excessive signaling
Negative modulators: Therapeutic potential
Clinical trials ongoing

Addiction

Critical for reward learning
Cocaine and nicotine effects
mGluR5 antagonists: Reduce craving

Therapeutic Approaches

Negative Allosteric Modulators (NAMs)

MPEP: First generation mGluR5 NAM
CTEP: Long-acting, brain-penetrant
Fenobam: Clinical candidate

Positive Allosteric Modulators (PAMs)

CPPHA: Enhances mGluR5 signaling
VU0360172: Highly selective

Clinical Potential

Alzheimer's disease: Symptomatic and disease-modifying
Fragile X: Restore synaptic function
Parkinson's: Reduce dyskinesias

Animal Models

Knockout Mice

mGluR5⁻/⁻ mice: Viable but behavioral abnormalities
Impaired learning and memory
Reduced anxiety

Transgenic

Human GRM5 expressing mice: Enhanced phenotypes
Disease models: Synaptic dysfunction

Research Directions

Selective compounds: More brain-penetrant NAMs
PET ligands: Imaging mGluR5 occupancy
Biomarkers: Receptor availability as marker
Gene therapy: Modulating expression

Background

The study of Mglur5 Protein — Glutamate Metabotropic Receptor 5 has evolved significantly over the past decades. Research in this area has revealed important insights into the underlying mechanisms of neurodegeneration and continues to drive therapeutic development.

Historical context and key discoveries in this field have shaped our current understanding and will continue to guide future research directions.

References

[[1]](https://pubmed.ncbi.nlm.nih.gov/10644993/) Conn PJ, et al. Metabotropic glutamate receptors. Annu Rev Pharmacol Toxicol. 2000.

[[2]](https://pubmed.ncbi.nlm.nih.gov/15622416/) Nicoletti F, et al. Metabotropic glutamate receptors. Neuropharmacology. 2011.

[[3]](https://pubmed.ncbi.nlm.nih.gov/21872611/) Cleva RM, et al. mGluR2/3 and mGluR5 in Parkinson's disease. Neuropharmacology. 2011.

[[4]](https://pubmed.ncbi.nlm.nih.gov/23480871/) Austin PJ, et al. mGluR2 receptors in neurodegenerative disease. J Neurochem. 2014.

[[5]](https://pubmed.ncbi.nlm.nih.gov/27069067/) Liu J, et al. mGluR2 in Alzheimer's disease. Front Cell Neurosci. 2016.

mGluR5 Protein — Glutamate Metabotropic Receptor 5

mGluR5 Protein

Introduction

mGluR5 Protein

Introduction

Overview

Protein Information

Structure

Normal Function

Calcium Signaling

Synaptic Plasticity

Learning and Memory

Role in Disease

Alzheimer's Disease

Parkinson's Disease

Fragile X Syndrome

Depression and Anxiety

Therapeutic Targeting

Key Publications

Expression Pattern

Signaling Mechanisms

Group I mGluR Signaling

Synaptic Localization

Role in Neurodegeneration

Alzheimer's Disease

Parkinson's Disease

Fragile X Syndrome

Addiction

Therapeutic Approaches

Negative Allosteric Modulators (NAMs)

Positive Allosteric Modulators (PAMs)

Clinical Potential

Animal Models

Knockout Mice

Transgenic

Research Directions

Background

References

See Also