mGluR5 Protein — Glutamate Metabotropic Receptor 5

mGluR5 Protein

<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

<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 — 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.

See Also

• [GRM5 Gene](/entities/grm5-gene)
• [Glutamate Receptors](/mechanisms/glutamatergic-signaling)
• [Amyloid Cascade](/mechanisms/amyloid-cascade)
• [Synaptic Dysfunction](/mechanisms/synaptic-dysfunction)
• [Alzheimer's Disease](/diseases/alzheimers-disease)