mGluR5 (Metabotropic Glutamate Receptor 5)

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mGluR5 (Metabotropic Glutamate Receptor 5)

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mGluR5 (Metabotropic Glutamate Receptor 5)

<div class="infobox">
<table>
<tr><td><strong>Gene</strong></td><td>GRM5</td></tr>
<tr><td><strong>UniProt</strong></td><td>[P41594](https://www.uniprot.org/uniprot/P41594)</td></tr>
<tr><td><strong>Molecular Weight</strong></td><td>132 kDa</td></tr>
<tr><td><strong>Subcellular Localization</strong></td><td>Plasma membrane, [Dendritic spines](/mechanisms/dendritic-spines)</td></tr>
<tr><td><strong>PDB Structures</strong></td><td>[6N51](https://www.rcsb.org/structure/6N51), [4OO9](https://www.rcsb.org/structure/4OO9)</td></tr>
<tr><td><strong>Aliases</strong></td><td>GRM5, mGlu5, MGLUR5</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>
</div>

Overview

...

mGluR5 (Metabotropic Glutamate Receptor 5)

<div class="infobox">
<table>
<tr><td><strong>Gene</strong></td><td>GRM5</td></tr>
<tr><td><strong>UniProt</strong></td><td>[P41594](https://www.uniprot.org/uniprot/P41594)</td></tr>
<tr><td><strong>Molecular Weight</strong></td><td>132 kDa</td></tr>
<tr><td><strong>Subcellular Localization</strong></td><td>Plasma membrane, [Dendritic spines](/mechanisms/dendritic-spines)</td></tr>
<tr><td><strong>PDB Structures</strong></td><td>[6N51](https://www.rcsb.org/structure/6N51), [4OO9](https://www.rcsb.org/structure/4OO9)</td></tr>
<tr><td><strong>Aliases</strong></td><td>GRM5, mGlu5, MGLUR5</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>
</div>

Overview

Mermaid diagram (expand to render)

mGluR5 (metabotropic glutamate receptor 5) is a G-protein-coupled receptor (GPCR) that mediates slow, modulatory glutamate signaling in the central nervous system. As a member of the Group I metabotropic glutamate receptors, mGluR5 couples to Gq proteins to activate phospholipase C and intracellular calcium signaling. mGluR5 plays critical roles in synaptic plasticity, learning, and memory, and has emerged as a promising therapeutic target in Alzheimer's disease, Parkinson's disease, and other neurodegenerative conditions.[@niswender2010]

Structure and Domains

mGluR5 is a Class C GPCR with a distinctive architecture:[@koehl2019]

Domain organization:

Venus flytrap domain (VFT): Large extracellular N-terminal domain that binds glutamate
Cysteine-rich domain (CRD): Connects VFT to transmembrane domain
Seven transmembrane domain (7TM): Classic GPCR domain for G-protein coupling
Intracellular C-terminal tail: Contains phosphorylation sites and protein interaction motifs

Functional dimer:

mGluR5 functions as an obligate homodimer (or heterodimer with mGluR1)
Dimerization occurs through the VFT domain
Two glutamate binding sites per dimer
Cooperative activation mechanism

Allosteric binding sites:

Orthosteric site: Glutamate binding in VFT domain
Allosteric sites: Multiple modulatory sites in 7TM domain (MPEP site, etc.)

Normal Function

mGluR5 mediates modulatory glutamate signaling:[@lscher2010]

Signal transduction pathway:

Glutamate → mGluR5 → Gq → PLCβ → IP3 + DAG →
IP3R → Ca²⁺ release from ER → PKC activation

Synaptic functions:

[Long-term potentiation](/mechanisms/long-term-potentiation) (LTP): Perisynaptic mGluR5 facilitates LTP induction
Long-term depression (LTD): mGluR5-dependent LTD at certain synapses
Synaptic protein synthesis: Links to local translation machinery
Metaplasticity: Modulates thresholds for plasticity induction

Neuronal excitability:

Modulates [NMDA receptor](/entities/nmda-receptor) function
Regulates voltage-gated calcium channels
Influences neuronal intrinsic excitability

Brain distribution:

High expression in striatum, [hippocampus](/brain-regions/hippocampus), [cortex](/brain-regions/cortex)
Particularly enriched in medium spiny [neurons](/entities/neurons) of striatum
Located perisynaptically (near, but not within, synapses)

Role in Neurodegeneration

Alzheimer's Disease

mGluR5 has complex roles in AD pathophysiology:[@um2013]

Pathogenic mechanisms:

mGluR5 can act as a co-receptor for [Aβ](/proteins/amyloid-beta) oligomers
Aβ-mGluR5 interaction triggers pathological signaling
Promotes synaptic dysfunction and spine loss
May contribute to [tau](/proteins/tau) hyperphosphorylation via [GSK-3β](/entities/gsk3-beta) activation

Protective mechanisms:

Normal mGluR5 function supports synaptic plasticity
mGluR5-mediated protein synthesis supports memory
Loss of mGluR5 function may contribute to cognitive decline

Therapeutic targeting:

Negative allosteric modulators (NAMs) show promise in animal models
MPEP and analogues reduce Aβ toxicity
Balance between therapeutic inhibition and preserving normal function[@hamilton2016]

Parkinson's Disease

mGluR5 is a validated target in PD:[@morin2013]

Motor symptoms:

mGluR5 antagonism reduces motor symptoms in PD models
Indirect pathway striatal neurons express high mGluR5
Reduces excessive glutamatergic transmission
Works synergistically with L-DOPA

L-DOPA-induced dyskinesias:

mGluR5 NAMs reduce dyskinesia severity
Dipraglurant showed efficacy in clinical trials
May allow lower L-DOPA doses

Neuroprotection:

mGluR5 inhibition may protect dopaminergic neurons
Reduces excitotoxic glutamate signaling
Anti-inflammatory effects via microglial mGluR5

Huntington's Disease

mGluR5 in HD:[@ribeiro2014]

Altered mGluR5 expression and signaling in HD striatum
Mutant [huntingtin](/proteins/huntingtin) affects mGluR5 membrane expression
mGluR5 NAMs show benefit in HD animal models
Reduce striatal neuron degeneration

Fragile X Syndrome and Autism

While not neurodegenerative, these conditions inform mGluR5 biology:

mGluR5 theory of fragile X: excessive mGluR5 signaling
mGluR5 NAMs in clinical trials for fragile X
Relevance to cognitive aspects of neurodegeneration

Therapeutic Targeting

Drug Development

mGluR5 modulators in development:[@gregory2021]

| Compound | Type | Status | Indication |
|----------|------|--------|------------|
| MPEP | NAM (research) | Preclinical | Research tool |
| Fenobam | NAM | Phase II | Anxiety, Fragile X |
| Dipraglurant | NAM | Phase II | PD dyskinesia |
| Basimglurant | NAM | Phase II | Depression, Fragile X |
| CTIEP | NAM | Discontinued | Fragile X |
| CDPPB | PAM (research) | Preclinical | Cognitive enhancement |

Clinical Trial Results

Parkinson's Disease:

Dipraglurant reduced L-DOPA-induced dyskinesia in Phase II
Well-tolerated, good safety profile
Moving to Phase III development

Fragile X (informative for cognition):

Mixed results with mGluR5 NAMs
May have been underdosed
Ongoing research continues

Mechanism-Based Considerations

NAMs vs Antagonists:

NAMs reduce but don't completely block receptor
Preserve basal signaling while reducing overactivation
Allosteric site provides selectivity

PAMs (Positive Allosteric Modulators):

Enhance receptor function
Potential for cognitive enhancement in AD
Risk of overactivation and excitotoxicity

Protein Interactions

| Interacting Partner | Function | Relevance |
|---------------------|----------|-----------|
| Gq/11 | G-protein coupling | Primary signaling |
| Homer proteins | Scaffold, coupling | Links to mGluR1, NMDAR |
| NMDA receptors | Co-modulation | Synaptic plasticity |
| PLCβ | Effector enzyme | IP3/DAG production |
| Aβ oligomers | Pathological ligand | AD toxicity |
| PKC | Phosphorylation | Desensitization |

Key Publications

[Conn PJ, et al., Metabotropic glutamate receptors in the basal ganglia (2005)](https://doi.org/10.1016/j.tips.2004.12.003) — Trends in Pharmacological Sciences. Comprehensive review of mGluR5 in basal ganglia.

[Um et al., Metabotropic glutamate receptor 5 is a coreceptor for Alzheimer Aβ oligomer (2013)](https://doi.org/10.1016/j.neuron.2012.11.004) — Neuron. Establishes mGluR5 as Aβ co-receptor.

[Morin et al., mGluR5 in Parkinson's disease (2013)](https://doi.org/10.1016/j.neuropharm.2013.04.018) — Neuropharmacology. Reviews mGluR5 as PD therapeutic target.

[Trenque et al., mGluR5 NAM dipraglurant in Parkinson's disease (2021)](https://pubmed.ncbi.nlm.nih.gov/33607834/) — Clinical trial results.

[Ribeiro et al., mGluR5 in neurodegeneration (2017)](https://doi.org/10.1007/s13311-017-0566-7) — Neurotherapeutics. Comprehensive review.

References

[Niswender CM, Conn PJ, Metabotropic glutamate receptors: physiology, pharmacology, and disease (2010)](https://doi.org/10.1146/annurev.pharmtox.011008.145533)

[Koehl A, et al, Structural insights into the activation of metabotropic glutamate receptors (2019)](https://doi.org/10.1038/s41586-019-0949-0)

[Lüscher C, Huber KM, Group 1 mGluR-dependent synaptic long-term depression: mechanisms and implications for circuitry and disease (2010)](https://doi.org/10.1016/j.neuron.2010.01.016)

[Um JW, et al, Metabotropic glutamate receptor 5 is a coreceptor for Alzheimer Aβ oligomer linked to synaptic dysfunction (2013)](https://doi.org/10.1016/j.neuron.2013.08.008)

[Hamilton A, et al, Pharmacological inhibition of mGluR5 restores cognitive function in a mouse model of Down syndrome (2016)](https://doi.org/10.1016/j.neuropharm.2016.07.006)

[Morin N, et al, mGlu5 receptor antagonist for L-DOPA-induced dyskinesia (2013)](https://doi.org/10.1016/j.neuropharm.2013.04.018)

[Ribeiro FM, et al, Metabotropic glutamate receptor 5 signalling promotes autophagy and is required for neuronal health (2014)](https://doi.org/10.1096/fj.14-254540)

[Gregory KJ, et al, Allosteric modulation of metabotropic glutamate receptors: structural insights and therapeutic potential (2021)](https://doi.org/10.1016/j.neuropharm.2021.108278)

Pathway Diagram

The following diagram shows the key molecular relationships involving mGluR5 (Metabotropic Glutamate Receptor 5) discovered through SciDEX knowledge graph analysis:

Mermaid diagram (expand to render)

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Related Entities

GRM5

▸Metadataorigin_type: v1_polymorphic_backfill

slug	proteins-grm5
kg_node_id	GRM5
entity_type	protein
origin_type	v1_polymorphic_backfill
source_table	wiki_pages
wiki_page_id	wp-39106912df7d
__merged_from	{'merged_at': '2026-05-13', 'unprefixed_id': 'proteins-grm5'}
_schema_version	1

📊 Evidence Profile

Evidence Balance

+0%

Certainty

45%

Debates

0

Incoming

9

Outgoing

18

0 supporting 0 contradicting 0 neutral

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📗 Cite This Artifact

mGluR5 (Metabotropic Glutamate Receptor 5)

mGluR5 (Metabotropic Glutamate Receptor 5)

Overview

mGluR5 (Metabotropic Glutamate Receptor 5)

Overview

Structure and Domains

Normal Function

Role in Neurodegeneration

Alzheimer's Disease

Parkinson's Disease

Huntington's Disease

Fragile X Syndrome and Autism

Therapeutic Targeting

Drug Development

Clinical Trial Results

Mechanism-Based Considerations

Protein Interactions

Key Publications

See Also

References

Pathway Diagram

💬 Discussion