| Gene | GRM5 |
| UniProt | [P41594](https://www.uniprot.org/uniprot/P41594) |
| Molecular Weight | 132 kDa |
| Subcellular Localization | Plasma membrane, [Dendritic spines](/mechanisms/dendritic-spines) |
| PDB Structures | [6N51](https://www.rcsb.org/structure/6N51), [4OO9](https://www.rcsb.org/structure/4OO9) |
| Aliases | GRM5, mGlu5, MGLUR5 |
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.[1]
mGluR5 is a Class C GPCR with a distinctive architecture:[2]
Domain organization:
Functional dimer:
Allosteric binding sites:
mGluR5 mediates modulatory glutamate signaling:[3]
Signal transduction pathway:
Glutamate → mGluR5 → Gq → PLCβ → IP3 + DAG →
IP3R → Ca²⁺ release from ER → PKC activation
Synaptic functions:
Neuronal excitability:
Brain distribution:
mGluR5 has complex roles in AD pathophysiology:[4]
Pathogenic mechanisms:
Protective mechanisms:
Therapeutic targeting:
mGluR5 is a validated target in PD:[6]
Motor symptoms:
L-DOPA-induced dyskinesias:
Neuroprotection:
mGluR5 in HD:[7]
While not neurodegenerative, these conditions inform mGluR5 biology:
mGluR5 modulators in development:[8]
| 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 |
Parkinson's Disease:
Fragile X (informative for cognition):
NAMs vs Antagonists:
PAMs (Positive Allosteric Modulators):
| 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 |
Conn PJ, et al., Metabotropic glutamate receptors in the basal ganglia (2005) — 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) — Neuron. Establishes mGluR5 as Aβ co-receptor.
Morin et al., mGluR5 in Parkinson's disease (2013) — Neuropharmacology. Reviews mGluR5 as PD therapeutic target.
Trenque et al., mGluR5 NAM dipraglurant in Parkinson's disease (2021) — Clinical trial results.
Ribeiro et al., mGluR5 in neurodegeneration (2017) — Neurotherapeutics. Comprehensive review.
Niswender CM, Conn PJ. Metabotropic glutamate receptors: physiology, pharmacology, and disease. Annual Review of Pharmacology and Toxicology. 2010. ↩︎
Koehl A, et al. Structural insights into the activation of metabotropic glutamate receptors. Nature. 2019. ↩︎
Lüscher C, Huber KM. Group 1 mGluR-dependent synaptic long-term depression: mechanisms and implications for circuitry and disease. Neuron. 2010. ↩︎
Um JW, et al. Metabotropic glutamate receptor 5 is a coreceptor for Alzheimer Aβ oligomer linked to synaptic dysfunction. Neuron. 2013. ↩︎
Hamilton A, et al. Pharmacological inhibition of mGluR5 restores cognitive function in a mouse model of Down syndrome. Neuropharmacology. 2016. ↩︎
Morin N, et al. mGlu5 receptor antagonist for L-DOPA-induced dyskinesia. Neuropharmacology. 2013. ↩︎
Ribeiro FM, et al. Metabotropic glutamate receptor 5 signalling promotes autophagy and is required for neuronal health. FASEB Journal. 2014. ↩︎
Gregory KJ, et al. Allosteric modulation of metabotropic glutamate receptors: structural insights and therapeutic potential. Neuropharmacology. 2021. ↩︎