GRM1

Summary

GRM1 (glutamate metabotropic receptor 1, HGNC:4593) is a protein-coding gene on chromosome 6q24.3, encoding Metabotropic glutamate receptor 1 (Q13255). G-protein coupled receptor for glutamate.

This gene encodes a metabotropic glutamate receptor that functions by activating phospholipase C. L-glutamate is the major excitatory neurotransmitter in the central nervous system and activates both ionotropic and metabotropic glutamate receptors. Glutamatergic neurotransmission is involved in most aspects of normal brain function and can be perturbed in many neuropathologic conditions. The canonical alpha isoform of the encoded protein is a disulfide-linked homodimer whose activity is mediated by a G-protein-coupled phosphatidylinositol-calcium second messenger system. This gene may be associated with many disease states, including schizophrenia, bipolar disorder, depression, and breast cancer. Alternative splicing results in multiple transcript variants encoding different isoforms.

Source: NCBI Gene 2911 — RefSeq curated summary.

At a glance

• Gene–disease (curated): autosomal recessive spinocerebellar ataxia 13 (Strong, GenCC) — +1 more curated relationship
• GWAS associations: 4
• Clinical variants (ClinVar): 445 total — 8 pathogenic, 5 likely-pathogenic
• Phenotypes (HPO): 45
• Druggable target: yes — 2 molecules with ChEMBL bioactivity
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity unscored
• MANE Select transcript: NM_001278064

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:4593
Approved symbol	GRM1
Name	glutamate metabotropic receptor 1
Location	6q24.3
Locus type	gene with protein product
Status	Approved
Aliases	GPRC1A, mGlu1, MGLUR1, PPP1R85
Ensembl gene	ENSG00000152822
Ensembl biotype	protein_coding
OMIM	604473
Entrez	2911

Gene structure

Transcript identifiers

Ensembl transcripts: 11 — 9 protein_coding, 2 retained_intron

ENST00000282753, ENST00000355289, ENST00000361719, ENST00000492807, ENST00000502405, ENST00000507005, ENST00000507907, ENST00000706833, ENST00000706834, ENST00000706835, ENST00000706836

RefSeq mRNA: 4 — MANE Select: NM_001278064 NM_001278064, NM_001278065, NM_001278066, NM_001278067

CCDS: CCDS47497, CCDS5209, CCDS64548

Canonical transcript exons

ENST00000282753 — 8 exons

Exon	Start	End
ENSE00000975751	146159348	146159597
ENSE00001084909	146352250	146352496
ENSE00001084910	146386890	146387016
ENSE00001084911	146304611	146304846
ENSE00001084916	146357526	146357694
ENSE00003846875	146029062	146030217
ENSE00003849436	146433872	146437601
ENSE00003997117	146398769	146399699

Expression profiles

Bgee: expression breadth broad, 94 present calls, max score 90.97.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.9006 / max 157.7546, expressed in 98 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
70355	0.6894	92
70354	0.1049	52
70356	0.0708	18
70357	0.0222	6
70358	0.0132	4

Top tissues by expression

266 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
lateral nuclear group of thalamus	UBERON:0002736	90.97	gold quality
cerebellar vermis	UBERON:0004720	89.48	gold quality
middle temporal gyrus	UBERON:0002771	87.86	gold quality
endothelial cell	CL:0000115	85.53	gold quality
cerebellum	UBERON:0002037	85.00	gold quality
Brodmann (1909) area 23	UBERON:0013554	84.73	gold quality
cerebellar cortex	UBERON:0002129	83.97	gold quality
cerebellar hemisphere	UBERON:0002245	83.76	gold quality
paraflocculus	UBERON:0005351	83.76	gold quality
right hemisphere of cerebellum	UBERON:0014890	82.66	gold quality
pons	UBERON:0000988	81.98	gold quality
cranial nerve II	UBERON:0000941	81.64	gold quality
superior frontal gyrus	UBERON:0002661	79.73	gold quality
Brodmann (1909) area 46	UBERON:0006483	78.52	gold quality
postcentral gyrus	UBERON:0002581	78.40	gold quality
entorhinal cortex	UBERON:0002728	77.96	gold quality
orbitofrontal cortex	UBERON:0004167	77.41	silver quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	77.24	gold quality
parietal lobe	UBERON:0001872	77.05	gold quality
prefrontal cortex	UBERON:0000451	75.24	gold quality
cortical plate	UBERON:0005343	74.57	gold quality
frontal cortex	UBERON:0001870	74.10	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	73.30	gold quality
cerebral cortex	UBERON:0000956	73.12	gold quality
neocortex	UBERON:0001950	73.03	gold quality
frontal pole	UBERON:0002795	72.72	silver quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	72.65	gold quality
middle frontal gyrus	UBERON:0002702	72.41	gold quality
Brodmann (1909) area 9	UBERON:0013540	72.36	gold quality
medial globus pallidus	UBERON:0002477	71.54	silver quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-HCAD-35	yes	689.46
E-ANND-3	yes	5.56

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): NR1I2

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity Not yet evaluated (unscored). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• In patients with mesial temporal lobe epilepsy, mGluR1 may increase hippocampal excitability through postsynaptic activation. (PMID:11951051)
• internalization of mGluR1 splice variants is subject to PKC and CaMKII regulation. (PMID:11961129)
• identification of crucial residues for setting the activated state (PMID:12444084)
• Melanoma model implicates metabotropic glutamate signaling in melanocytic neoplasia. (PMID:12704387)
• PKA activation inhibits the agonist-induced internalization and desensitization of mGluR1a and mGluR1b, probably by reducing their interaction with GRK2 and nonvisual arrestins. (PMID:15155843)
• metabotropic glutamate receptors 1 and 5 mediate opposite glutamate effects in human lymphocyte activation (PMID:15184389)
• Stimulation of glial mGluR1 through mediators present in the cerebrospinal fluid may contribute to glial proliferation and astrogliosis in amyotrophic lateral sclerosis. (PMID:15330338)
• These results show that mGlu1alpha receptor interacts with caveolins and that this interaction is physiologically relevant for receptor function. (PMID:15383311)
• mutant/wild-type heterodimeric group I metabotropic glutamate receptors are inactive at ligand concentrations favoring glutamate association with receptor dimers at only one subunit (PMID:15466247)
• examined whether both heptahelical domains are turned on upon full receptor activation (PMID:15660124)
• kinase binding to an mGluR1 domain involved in G protein-coupling is essential for the phosphorylation-independent attenuation of signaling by GRK2 (PMID:15870073)
• This study found an increase in the expression of mGluR1a and mGluR2/3 immunoreactivity in the PFC in schizophrenia. (PMID:15945063)
• group I mGluRs/PLC signaling are down-regulated and desensitized in the frontal cortex in cDLB and AD cases and that these modifications worsen with progression of AD changes in the cerebral neocortex. (PMID:15949941)
• mGLuR1a signaling is attenuated by the huntingtin-binding protein optineurin (PMID:16091361)
• Human melanoma cells release elevated levels of glutamate, implying a possible autocrine loop via GRM1. (PMID:17332361)
• Results describe the structure of the Metabotropic glutamate receptor 1 (mGlu1)gene and demonstrated that mGlu1 transcription takes places at alternative first exons. (PMID:17430891)
• May contribute to melanoma susceptibility in a subgroup of patients with a low level of sun exposure and tumors located on the trunk and extremities. (PMID:17609672)
• Expression of mGluR1 increases in human with hypothalamic hamartoma and in the female monkey hypothalamus at puberty. (PMID:18059092)
• The proline-993-serine amino acid substitution is a highly frequent polymorphism in the human mGluR1 gene. (PMID:19146831)
• Present study points to ImGluR(V), a depolarization-activated inward current, as the cellular mechanism for group I mGluR-mediated epileptogenesis. (PMID:19295155)
• Amplification and sequencing of cDNA and genomic DNA allowed the identification of 10 nonsynonymous single nucleotide polymorphisms (nsSNPs) in tas1r1 (n = 3), tas1r3 (n = 3), and mGluR1 (n = 4). (PMID:19571223)
• the association of CAIN with intracellular domains involved in mGluR/G protein coupling provides a mechanism by which Group I mGluR endocytosis and signaling are regulated (PMID:19717561)
• Taken together, these results showed that, in addition to the MAPK pathway previously reported being a downstream target of stimulated Grm1, AKT2 is another downstream target in Grm1 mediated melanocyte transformation. (PMID:19843246)
• Absence of mutations in a relatively small cohort of patients appears to suggest that mutations in GRM1 are not frequent in cerebellar ataxias. (PMID:19924463)
• These findings show a differential expression pattern of mGluR1a and mGluR5, suggesting a role for both receptors in the early stages of corticogenesis with, however, a different contribution to human cortical developmental events. (PMID:20149785)
• Data reveal that Pyk2 couples the activation mGluRs to the ERK1/2 mitogen-activated protein kinase pathway even though it attenuates mGluR1-dependent G protein signaling. (PMID:20180987)
• Elucidation of a novel extracellular calcium-binding site on metabotropic glutamate receptor 1{alpha} (mGluR1{alpha}) that controls receptor activation. (PMID:20705606)
• Studies indicate that FXS has been linked to altered group I metabotropic glutamate receptor (mGluR)-dependent, and potential targeted therapeutic strategies developed to specifically correct disturbances in the excitatory mGluR. (PMID:20864408)
• Disruption of mGluR1 signaling at parallel fiber-Purkinje cell synapses is a major synaptic defect in homozygous staggerer mice, correlating with spinocerebellar ataxia (SCA) type 1 pathology in the extreme mouse model. (PMID:21558162)
• analysis of clustered coding variants in the glutamate receptor complexes of individuals with schizophrenia and bipolar disorder (PMID:21559497)
• Observations implicate mGluR1 and glutamate signaling as a promising new molecular target for the treatment of breast cancer. (PMID:21681448)
• Within the GRM1 locus, 22 SNPs showed nominally significant association with UPD, of which 6 withstood corrections for multiple testing. (PMID:21962378)
• These data indicate group I mGluRs are highly expressed on oligodendrocytes during the peak period of vulnerability to HI and modulation of mGluRs is protective in a rodent model of periventricular leukomalacia. (PMID:22169210)
• Deleterious GRM1 mutations are associated with schizophrenia. (PMID:22448230)
• This study demonistrated that childhood-onset mood disorders and suicide attempt association between HOMER1 rs2290639 and between NPTX2 markers rs705315 and rs1681248. (PMID:22460132)
• Normal, non-mutated CFTR, as well as mutated forms of CFTR were associated with metabotropic mGluR1. (PMID:22520513)
• demethylation within the promoter region of GRM1 may also be a mechanism for the derepression of mGluR1 expression in melanocytes that progress to cell transformation and tumor formation. (PMID:22771868)
• Suppression of GRM1 expression in several human melanoma cell lines resulted in a reduction in the number of viable cells and a decrease in stimulated mitogen-activated protein kinase (MAPK) and PI3K/AKT and suppressed tumor progression in vivo. (PMID:22798429)
• Only a single subunit assumes an active state in an mGluR1 receptor dimer. (PMID:22894836)
• The study implicates mGluR1 in human hereditary ataxia. (PMID:22901947)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	grm1a	ENSDARG00000026796
danio_rerio	grm1b	ENSDARG00000098320
mus_musculus	Grm1	ENSMUSG00000019828
rattus_norvegicus	Grm1	ENSRNOG00000014290
caenorhabditis_elegans	mgl-2	WBGENE00003233

Paralogs (7): GRM6 (ENSG00000113262), GRM4 (ENSG00000124493), GRM2 (ENSG00000164082), GRM5 (ENSG00000168959), GRM8 (ENSG00000179603), GRM7 (ENSG00000196277), GRM3 (ENSG00000198822)

Protein

Protein identifiers

Metabotropic glutamate receptor 1 — Q13255 (reviewed: Q13255)

All UniProt accessions (1): Q13255

UniProt curated annotations — full annotation on UniProt →

Function. G-protein coupled receptor for glutamate. Ligand binding causes a conformation change that triggers signaling via guanine nucleotide-binding proteins (G proteins) and modulates the activity of down-stream effectors. Signaling activates a phosphatidylinositol-calcium second messenger system. May participate in the central action of glutamate in the CNS, such as long-term potentiation in the hippocampus and long-term depression in the cerebellum. May function in the light response in the retina. Induces GRID1 and GRID2 cation-channel activation via GNAQ-PLC-PKC pathway in dopaminergic neurons and cerebellar Purkinje cell, respectively.

Subunit / interactions. Homodimer; disulfide-linked. The PPXXF motif binds HOMER1, HOMER2 and HOMER3. Interacts with TAMALIN. Interacts with RYR1, RYR2, ITPR1, SHANK1 and SHANK3. Interacts with SIAH1.

Subcellular location. Cell membrane. Postsynaptic cell membrane. Cell projection. Dendrite.

Tissue specificity. Detected in brain.

Disease relevance. Spinocerebellar ataxia, autosomal recessive, 13 (SCAR13) [MIM:614831] A form of spinocerebellar ataxia, a clinically and genetically heterogeneous group of cerebellar disorders. Patients show progressive incoordination of gait and often poor coordination of hands, speech and eye movements, due to degeneration of the cerebellum with variable involvement of the brainstem and spinal cord. SCAR13 is characterized by delayed psychomotor development beginning in infancy. Affected individuals show mild to profound intellectual disability with poor or absent speech as well as gait and stance ataxia and hyperreflexia. The disease is caused by variants affecting the gene represented in this entry. Spinocerebellar ataxia 44 (SCA44) [MIM:617691] A form of spinocerebellar ataxia, a clinically and genetically heterogeneous group of cerebellar disorders. Patients show progressive incoordination of gait and often poor coordination of hands, speech and eye movements, due to degeneration of the cerebellum with variable involvement of the brainstem and spinal cord. SCA44 is a slowly progressive, autosomal dominant form. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Signaling is inhibited by the antagonist LY341495. The LY341495 binding site partially overlaps with the glutamate binding site. Signaling is also inhibited by synthetic allosteric regulators, such as FITM (4-fluoro-N-(4-(6-(isopropylamino)pyrimidin-4-yl)thiazol-2-yl)-N-methylbenzamide) that bind in a pocket between the transmembrane helices.

Similarity. Belongs to the G-protein coupled receptor 3 family.

Isoforms (3)

UniProt ID	Names	Canonical?
Q13255-1	Alpha	yes
Q13255-2	Beta
Q13255-3	3

RefSeq proteins (4): NP_001264993, NP_001264994, NP_001264995, NP_001264996 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000162	GPCR_3_mtglu_rcpt	Family
IPR000337	GPCR_3	Family
IPR001256	GPCR_3_mGluR1	Family
IPR001828	ANF_lig-bd_rcpt	Domain
IPR011500	GPCR_3_9-Cys_dom	Domain
IPR017978	GPCR_3_C	Domain
IPR017979	GPCR_3_CS	Conserved_site
IPR019588	Metabotropic_Glu_rcpt_Homer-bd	Domain
IPR028082	Peripla_BP_I	Homologous_superfamily
IPR038550	GPCR_3_9-Cys_sf	Homologous_superfamily
IPR050726	mGluR	Family

Pfam: PF00003, PF01094, PF07562, PF10606

UniProt features (121 total): helix 25, strand 22, sequence variant 11, turn 9, topological domain 8, modified residue 8, transmembrane region 7, binding site 6, disulfide bond 6, compositionally biased region 4, glycosylation site 4, splice variant 4, region of interest 3, sequence conflict 2, signal peptide 1, chain 1

Structure

Experimental structures (PDB)

8 structures.

PDB	Method	Resolution (Å)
3KS9	X-RAY DIFFRACTION	1.9
4OR2	X-RAY DIFFRACTION	2.8
9WQO	ELECTRON MICROSCOPY	2.9
9WQP	ELECTRON MICROSCOPY	3.2
9WQM	ELECTRON MICROSCOPY	3.3
7DGE	ELECTRON MICROSCOPY	3.65
9WQN	ELECTRON MICROSCOPY	3.7
7DGD	ELECTRON MICROSCOPY	3.96

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q13255-F1	71.38	0.45

Antibody-complex structures (SAbDab): 1 — 7DGE

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Ligand- & substrate-binding residues (6): 74; 165; 186–188; 236; 318; 409

Post-translational modifications (8): 853, 871, 894, 969, 1091, 1142, 1146, 1149

Disulfide bonds (6): 67–109, 140, 289–291, 378–394, 432–439, 657–746

Glycosylation sites (4): 98, 223, 397, 515

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-416476	G alpha (q) signalling events
R-HSA-420499	Class C/3 (Metabotropic glutamate/pheromone receptors)
R-HSA-6794361	Neurexins and neuroligins
R-HSA-9717207	Sensory perception of sweet, bitter, and umami (glutamate) taste

MSigDB gene sets: 289 (showing top): GOBP_BEHAVIOR, GOBP_RESPONSE_TO_ELECTRICAL_STIMULUS, RORA1_01, GOBP_REGULATION_OF_SYNAPTIC_TRANSMISSION_GLUTAMATERGIC, GOBP_POSITIVE_REGULATION_OF_MAPK_CASCADE, GOBP_G_PROTEIN_COUPLED_GLUTAMATE_RECEPTOR_SIGNALING_PATHWAY, GOBP_AMINO_ACID_TRANSMEMBRANE_TRANSPORT, GOBP_CELL_CELL_SIGNALING, GOBP_ORGANIC_ACID_TRANSPORT, GOBP_CELLULAR_RESPONSE_TO_ELECTRICAL_STIMULUS, GOBP_ADENYLATE_CYCLASE_MODULATING_G_PROTEIN_COUPLED_RECEPTOR_SIGNALING_PATHWAY, GOBP_SENSORY_PERCEPTION_OF_PAIN, GOBP_REGULATION_OF_POSTSYNAPTIC_MEMBRANE_POTENTIAL, KEGG_NEUROACTIVE_LIGAND_RECEPTOR_INTERACTION, GOBP_AMINO_ACID_TRANSPORT

GO Biological Process (18): G protein-coupled receptor signaling pathway (GO:0007186), phospholipase C-activating G protein-coupled receptor signaling pathway (GO:0007200), phospholipase C-activating G protein-coupled glutamate receptor signaling pathway (GO:0007206), G protein-coupled glutamate receptor signaling pathway (GO:0007216), chemical synaptic transmission (GO:0007268), locomotory behavior (GO:0007626), sensory perception of pain (GO:0019233), positive regulation of MAPK cascade (GO:0043410), regulation of sensory perception of pain (GO:0051930), regulation of synaptic transmission, glutamatergic (GO:0051966), cellular response to electrical stimulus (GO:0071257), L-glutamate import across plasma membrane (GO:0098712), synaptic signaling via neuropeptide (GO:0099538), signal transduction (GO:0007165), adenylate cyclase-inhibiting G protein-coupled glutamate receptor signaling pathway (GO:0007196), regulation of membrane potential (GO:0042391), regulation of postsynaptic membrane potential (GO:0060078), regulation of postsynaptic cytosolic calcium ion concentration (GO:0099566)

GO Molecular Function (7): adenylate cyclase inhibiting G protein-coupled glutamate receptor activity (GO:0001640), G protein-coupled receptor activity (GO:0004930), glutamate receptor activity (GO:0008066), obsolete G protein-coupled neurotransmitter receptor activity involved in regulation of postsynaptic cytosolic calcium ion concentration (GO:0098872), G protein-coupled receptor activity involved in regulation of postsynaptic membrane potential (GO:0099530), obsolete neurotransmitter receptor activity involved in regulation of postsynaptic cytosolic calcium ion concentration (GO:0099583), protein binding (GO:0005515)

GO Cellular Component (15): nucleus (GO:0005634), plasma membrane (GO:0005886), G protein-coupled receptor dimeric complex (GO:0038037), G protein-coupled receptor homodimeric complex (GO:0038038), dendriole (GO:0044293), Schaffer collateral - CA1 synapse (GO:0098685), postsynaptic density membrane (GO:0098839), glutamatergic synapse (GO:0098978), postsynaptic density (GO:0014069), membrane (GO:0016020), dendrite (GO:0030425), cell projection (GO:0042995), neuron projection (GO:0043005), synapse (GO:0045202), postsynaptic membrane (GO:0045211)

Reactome top-level categories

Rollup of top-4 pathways:

Category	Pathways
GPCR downstream signalling	1
GPCR ligand binding	1
Protein-protein interactions at synapses	1
Sensory perception of taste	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
G protein-coupled receptor signaling pathway	3
G protein-coupled receptor activity	2
G protein-coupled glutamate receptor signaling pathway	2
G protein-coupled glutamate receptor activity	2
postsynapse	2
transmembrane signaling receptor activity	2
postsynaptic membrane	2
synapse	2
cellular anatomical structure	2
signal transduction	1
phospholipase C activator activity	1
PLC activating G protein-coupled glutamate receptor activity	1
phospholipase C-activating G protein-coupled receptor signaling pathway	1
glutamate receptor signaling pathway	1
anterograde trans-synaptic signaling	1
behavior	1
sensory perception	1
MAPK cascade	1
regulation of MAPK cascade	1
positive regulation of intracellular signal transduction	1
sensory perception of pain	1
regulation of sensory perception	1
synaptic transmission, glutamatergic	1
modulation of chemical synaptic transmission	1
response to electrical stimulus	1
cellular response to abiotic stimulus	1
L-glutamate transmembrane transport	1
amino acid import across plasma membrane	1
synaptic signaling	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
adenylate cyclase inhibiting G protein-coupled glutamate receptor activity	1
adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway	1
monoatomic ion transmembrane transport	1
regulation of biological quality	1
regulation of membrane potential	1
regulation of cytosolic calcium ion concentration	1

Protein interactions and networks

STRING

2727 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
GRM1	GNAQ	P50148	985
GRM1	HOMER1	Q86YM7	971
GRM1	HOMER3	Q9NSC5	902
GRM1	HOMER2	Q9NSB8	893
GRM1	ESR1	P03372	888
GRM1	DLGAP1	P78335	866
GRM1	ITPR1	Q14643	855
GRM1	GRIA1	P42261	831
GRM1	TRPC1	P48995	791
GRM1	GRIA2	P42262	766
GRM1	SHANK1	Q9Y566	760
GRM1	GRIK1	P39086	758
GRM1	GRM5	P41594	728
GRM1	DLG4	P78352	705
GRM1	CYFIP1	Q7L576	692

IntAct

29 interactions, top by confidence:

A	B	Type	Score
KPNA1	GRM1	psi-mi:“MI:0915”(physical association)	0.520
USP7	GRM1	psi-mi:“MI:0407”(direct interaction)	0.440
GRM1	GRM1	psi-mi:“MI:0407”(direct interaction)	0.440
GRM1	ZMYM3	psi-mi:“MI:0915”(physical association)	0.400
GRM1	KPNA3	psi-mi:“MI:0915”(physical association)	0.400
GRM1	OPRM1	psi-mi:“MI:0915”(physical association)	0.370
CDH5	ESYT2	psi-mi:“MI:2364”(proximity)	0.270
AKT1	GRM1	psi-mi:“MI:2364”(proximity)	0.270
BRAF	GRM1	psi-mi:“MI:2364”(proximity)	0.270
FBXW7	GRM1	psi-mi:“MI:2364”(proximity)	0.270
GRM1	FBXW7	psi-mi:“MI:2364”(proximity)	0.270
SMAD4	GRM1	psi-mi:“MI:2364”(proximity)	0.270
GRM1	SMARCA4	psi-mi:“MI:2364”(proximity)	0.270
SMARCA4	GRM1	psi-mi:“MI:2364”(proximity)	0.270
SPOP	GRM1	psi-mi:“MI:2364”(proximity)	0.270
GRM1	SPOP	psi-mi:“MI:2364”(proximity)	0.270
GRM1	PTEN	psi-mi:“MI:2364”(proximity)	0.270
GRM1	TP53	psi-mi:“MI:2364”(proximity)	0.270

BioGRID (58): HOMER1 (Affinity Capture-Western), GRM1 (Affinity Capture-Western), GRM1 (Affinity Capture-Western), GRM1 (Affinity Capture-Western), GRM1 (Affinity Capture-Western), SRC (Affinity Capture-Western), FYN (Affinity Capture-Western), SYK (Affinity Capture-Western), GRM1 (Affinity Capture-Western), CCND2 (FRET), CD44 (FRET), CDKN2B (FRET), EPHA2 (FRET), FGFR4 (FRET), GRM1 (FRET)

ESM2 similar proteins: B3DIG4, O00144, O57328, O57329, O70421, O75084, O93274, P18537, P23385, P27115, P27808, P41594, P55013, P58421, P97772, Q08463, Q08464, Q13255, Q13467, Q14332, Q24760, Q498S8, Q5BL72, Q5RH73, Q61090, Q61091, Q6NVG7, Q6P9A2, Q6PA90, Q8AVJ9, Q8BKG4, Q8CHL0, Q8IYK4, Q8K4C8, Q9DEB5, Q9EQD0, Q9H461, Q9I9M5, Q9IA02, Q9IA06

Diamond homologs: O00222, O15303, O62714, P23385, P31421, P31422, P31423, P31424, P35349, P35400, P41180, P41594, P47743, P48442, P70579, P91685, P97772, Q09630, Q13255, Q14416, Q14831, Q14832, Q14833, Q14BI2, Q1ZZH0, Q1ZZH1, Q3UVX5, Q5NCH9, Q5RAL3, Q5RDQ8, Q68ED2, Q68EF4, Q863I4, Q9QY96, Q9QYS2, P35384, G5ECB2, O70410, O75899, O88871

SIGNOR signaling

5 interactions.

A	Effect	B	Mechanism
PRKCA	“down-regulates activity”	GRM1	phosphorylation
“glutamic acid”	“up-regulates activity”	GRM1	“chemical activation”
GRM1	“up-regulates activity”	GNAS	binding
GRM1	up-regulates	Excitatory_synaptic_transmission
GRM1	“up-regulates quantity”	calcium(2+)	relocalization

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 15 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

GO biological processes:

GO term	Partners	Fold	FDR
negative regulation of cell population proliferation	5	14.0×	3e-03
positive regulation of gene expression	5	12.9×	3e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

445 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	8
Likely pathogenic	5
Uncertain significance	228
Likely benign	115
Benign	48

Top pathogenic / likely-pathogenic (13)

Variant ID	HGVS	Classification
2446708	NM_001278064.2(GRM1):c.2471C>G (p.Thr824Arg)	Pathogenic
2572460	NM_001278064.2(GRM1):c.1715del (p.Asn572fs)	Pathogenic
438856	NM_001278064.2(GRM1):c.785A>G (p.Tyr262Cys)	Pathogenic
438857	NM_001278064.2(GRM1):c.3165dup (p.Gly1056fs)	Pathogenic
4532016	NM_001278064.2(GRM1):c.2238C>A (p.Cys746Ter)	Pathogenic
4723807	NM_001278064.2(GRM1):c.1679del (p.Phe560fs)	Pathogenic
626248	NM_001278064.2(GRM1):c.889C>T (p.Arg297Ter)	Pathogenic
984959	NM_001278064.2(GRM1):c.1360C>T (p.Leu454Phe)	Pathogenic
2440617	NM_001278064.2(GRM1):c.3030del (p.Lys1011fs)	Likely pathogenic
2440626	NM_001278064.2(GRM1):c.1974C>A (p.Tyr658Ter)	Likely pathogenic
3337255	NM_001278064.2(GRM1):c.2527_2548del (p.Glu843fs)	Likely pathogenic
3362552	NM_001278064.2(GRM1):c.1145del (p.Gly382fs)	Likely pathogenic
438855	NM_001278064.2(GRM1):c.2375A>G (p.Tyr792Cys)	Likely pathogenic

SpliceAI

3675 predictions. Top by Δscore:

Variant	Effect	Δscore
6:146092770:G:GT	donor_gain	1.0000
6:146092770:G:T	donor_gain	1.0000
6:146159593:GGAAG:G	donor_gain	1.0000
6:146159594:GAAG:G	donor_gain	1.0000
6:146159594:GAAGG:G	donor_gain	1.0000
6:146159595:AAG:A	donor_gain	1.0000
6:146159596:AG:A	donor_gain	1.0000
6:146159596:AGG:A	donor_loss	1.0000
6:146159597:GG:G	donor_gain	1.0000
6:146159598:G:GG	donor_gain	1.0000
6:146304609:A:AG	acceptor_gain	1.0000
6:146304610:G:GG	acceptor_gain	1.0000
6:146352444:G:GT	donor_gain	1.0000
6:146352459:G:GT	donor_gain	1.0000
6:146352494:A:T	donor_gain	1.0000
6:146357691:TAAGG:T	donor_loss	1.0000
6:146357693:AGGT:A	donor_loss	1.0000
6:146357695:G:A	donor_loss	1.0000
6:146357696:T:A	donor_loss	1.0000
6:146387012:AACAG:A	donor_loss	1.0000
6:146387013:ACAGG:A	donor_loss	1.0000
6:146387014:CAGGT:C	donor_loss	1.0000
6:146387015:AGG:A	donor_loss	1.0000
6:146387016:GG:G	donor_loss	1.0000
6:146387017:G:GA	donor_loss	1.0000
6:146387018:T:G	donor_loss	1.0000
6:146399700:G:GG	donor_gain	1.0000
6:146426642:GT:G	donor_gain	1.0000
6:146092761:G:GT	donor_gain	0.9900
6:146092840:T:G	donor_gain	0.9900

AlphaMissense

7837 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
6:146029659:G:A	G48R	1.000
6:146029659:G:C	G48R	1.000
6:146029660:G:A	G48E	1.000
6:146029663:C:A	A49D	1.000
6:146029666:T:A	L50H	1.000
6:146029666:T:C	L50P	1.000
6:146029675:T:A	V53D	1.000
6:146029677:C:G	H54D	1.000
6:146029678:A:C	H54P	1.000
6:146029716:T:A	C67S	1.000
6:146029716:T:C	C67R	1.000
6:146029717:G:A	C67Y	1.000
6:146029717:G:C	C67S	1.000
6:146029717:G:T	C67F	1.000
6:146029718:T:G	C67W	1.000
6:146029740:G:C	G75R	1.000
6:146029740:G:T	G75C	1.000
6:146029741:G:A	G75D	1.000
6:146029741:G:T	G75V	1.000
6:146029750:G:T	R78M	1.000
6:146029751:G:C	R78S	1.000
6:146029751:G:T	R78S	1.000
6:146029758:G:C	A81P	1.000
6:146029821:G:C	G102R	1.000
6:146029822:G:A	G102D	1.000
6:146029834:G:C	R106P	1.000
6:146029836:G:C	D107H	1.000
6:146029836:G:T	D107Y	1.000
6:146029837:A:C	D107A	1.000
6:146029837:A:G	D107G	1.000

dbSNP variants (sampled 300 via entrez): RS1000008464 (6:146372888 T>C), RS1000009249 (6:146414559 C>A,T), RS1000022436 (6:146164517 G>C), RS1000023533 (6:146379872 C>G), RS1000025958 (6:146432287 A>G), RS1000027713 (6:146251253 C>T), RS1000031009 (6:146292503 A>G), RS1000032446 (6:146086998 G>A), RS1000041678 (6:146414648 C>T), RS1000046780 (6:146033428 CTG>C), RS1000054130 (6:146062285 A>C), RS1000064872 (6:146297738 A>G,T), RS1000081661 (6:146039043 T>G), RS1000086233 (6:146422350 A>G), RS1000098808 (6:146033157 T>A)

Disease associations

OMIM: gene MIM:604473 | disease phenotypes: MIM:617691, MIM:614831

GenCC curated gene-disease

Disease	Classification	Inheritance
autosomal recessive spinocerebellar ataxia 13	Strong	Autosomal recessive
spinocerebellar ataxia 44	Strong	Autosomal dominant

Mondo (4): spinocerebellar ataxia 44 (MONDO:0033479), autosomal recessive spinocerebellar ataxia 13 (MONDO:0013905), cerebellar ataxia (MONDO:0000437), intellectual disability (MONDO:0001071)

Orphanet (4): Spinocerebellar ataxia type 44 (Orphanet:631095), Autosomal recessive congenital cerebellar ataxia due to MGLUR1 deficiency (Orphanet:324262), Rare ataxia (Orphanet:102002), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

45 total (30 of 45 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000360	Tinnitus
HP:0000486	Strabismus
HP:0000508	Ptosis
HP:0000565	Esotropia
HP:0000571	Hypometric saccades
HP:0000640	Gaze-evoked nystagmus
HP:0000750	Delayed speech and language development
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001251	Ataxia
HP:0001257	Spasticity
HP:0001260	Dysarthria
HP:0001263	Global developmental delay
HP:0001270	Motor delay
HP:0001271	Polyneuropathy
HP:0001272	Cerebellar atrophy
HP:0001310	Dysmetria
HP:0001337	Tremor
HP:0001344	Absent speech
HP:0001347	Hyperreflexia
HP:0001348	Brisk reflexes
HP:0002015	Dysphagia
HP:0002066	Gait ataxia
HP:0002075	Dysdiadochokinesis
HP:0002167	Abnormal speech pattern
HP:0002198	Dilated fourth ventricle
HP:0002359	Frequent falls
HP:0002406	Limb dysmetria

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST003073_14	Cerebral amyloid deposition (PET imaging)	3.000000e-06
GCST003073_4	Cerebral amyloid deposition (PET imaging)	6.000000e-07
GCST005872_1	Waist circumference	1.000000e-06
GCST008772_3	Suicide	4.000000e-07

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0007707	cerebral amyloid deposition measurement
EFO:0007624	suicide

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D002524	Cerebellar Ataxia	C10.228.140.252.190; C10.597.350.090.500; C23.888.592.350.090.200
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL3772 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

2 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 932,606 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL575060	GLUTAMIC ACID	3	929,756
CHEMBL239800	FENOBAM ANHYDROUS	2	2,850

PharmGKB: 1 entry (VIP=true, CPIC=false)

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: gpcr — Metabotropic glutamate receptors

Most potent curated ligand interactions (78 total), top 25:

Ligand	Action	Affinity	Parameter
[11C]JNJ-16567083	Antagonist	9.06	pKi
compound 11q [PMID: 19433355]	Negative	9.05	pIC50
[3H]R214127	Negative	9.0	pKd
NPS2390	Negative	8.9	pKi
JNJ16259685	Negative	8.9	pIC50
JNJ-16567083	Negative	8.85	pKi
compound 23i [PMID: 17929793]	Negative	8.85	pIC50
compound 11s [PMID: 19433355]	Negative	8.68	pIC50
compound 23h [PMID: 17929793]	Negative	8.66	pIC50
compound 23c [PMID: 17929793]	Negative	8.6	pIC50
CFMTI	Negative	8.59	pIC50
compound 23e [PMID: 17929793]	Negative	8.54	pIC50
A-794282	Negative	8.52	pIC50
compound 22 [PMID: 19289283]	Negative	8.52	pIC50
[18F]MK-1312	Negative	8.44	pIC50
compound 22 [PMID: 17276684]	Negative	8.44	pKi
MK-5435	Negative	8.37	pIC50
compound 11c [PMID: 17929793]	Negative	8.31	pIC50
[18F]FITM	Negative	8.29	pIC50
FITM	Negative	8.27	pKi
[18F]FPIT	Negative	8.27	pIC50
FTIDC	Negative	8.24	pIC50
compound 32 [PMID: 19289283]	Negative	8.22	pIC50
compound 10i [PMID: 23084894]	Negative	8.22	pIC50
[3H]EM-TBPC	Positive	8.2	pKd

Binding affinities (BindingDB)

145 measured of 251 human assays (266 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
(2S,4aR,6aR,7R,9S,10aS,10bR)-9-(acetyloxy)-2-(furan-3-yl)dodecahydro-6a,10b-dimethyl-4,10-dioxo-2H-naphtho-[2,1-c]pyran-7-carboxylic acid methyl ester	EC50	0.3 nM
9-bromo-2-thiophen-2-yl-7,8-dihydro-4H-[1,4]diazepino[7,1-a]isoquinolin-5-one	IC50	8 nM	US-8853203: Diazepinone derivatives
(RS)-2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)-propionicacid	KI	12 nM
9-methoxy-2-thiophen-2-yl-7,8-dihydro-4H-[1,4]diazepino[7,1-a]isoquinolin-5-one	IC50	15 nM	US-8853203: Diazepinone derivatives
9-iodo-2-(1-propan-2-ylpyrazol-4-yl)-7,8-dihydro-4H-[1,4]diazepino[7,1-a]isoquinolin-5-one	IC50	15 nM	US-8853203: Diazepinone derivatives
9-ethynyl-2-thiophen-2-yl-7,8-dihydro-4H-[1,4]diazepino[7,1-a]isoquinolin-5-one	IC50	22 nM	US-8853203: Diazepinone derivatives
9-chloro-2-thiophen-2-yl-7,8-dihydro-4H-[1,4]diazepino[7,1-a]isoquinolin-5-one	IC50	27 nM	US-8853203: Diazepinone derivatives
9-iodo-2-(1-methylpyrazol-4-yl)-7,8-dihydro-4H-[1,4]diazepino[7,1-a]isoquinolin-5-one	IC50	35 nM	US-9650377: Diazepinone derivatives
9-cyclopropyl-2-[4-(2-hydroxyethyl)imidazol-1-yl]-7,8-dihydro-4H-[1,4]diazepino[7,1-a]isoquinolin-5-one	IC50	41 nM	US-8853203: Diazepinone derivatives
9-dimethylamino-3-(1-adamantyl)-3H-5-thia-1,3,6-triazafluoren-4-one	IC50	76 nM
2-(furan-3-yl)-9-iodo-7,8-dihydro-4H-[1,4]diazepino[7,1-a]isoquinolin-5-one	IC50	93 nM	US-8853203: Diazepinone derivatives
CHEMBL2418380	IC50	93 nM
CHEMBL2397347	IC50	98 nM
Adamantan-1-yl-[2-(6-morpholin-4-yl-2-pyridin-3-yl)-cyclopropyl]-methanone	KI	110 nM
2-thiophen-2-yl-9-(trifluoromethyl)-7,8-dihydro-4H-[1,4]diazepino[7,1-a]isoquinolin-5-one	IC50	150 nM	US-8853203: Diazepinone derivatives
CHEMBL2397349	IC50	161 nM
CHEMBL2397351	IC50	166 nM
2-(4-ethylimidazol-1-yl)-9-(furan-2-yl)-7,8-dihydro-4H-[1,4]diazepino[7,1-a]isoquinolin-5-one	IC50	170 nM	US-8853203: Diazepinone derivatives
CHEMBL2418383	IC50	185 nM
9-methoxy-2-(5-methylfuran-2-yl)-7,8-dihydro-4H-[1,4]diazepino[7,1-a]isoquinolin-5-one	IC50	210 nM	US-8853203: Diazepinone derivatives
9-cyclobutyl-2-[4-(methoxymethyl)imidazol-1-yl]-7,8-dihydro-4H-[1,4]diazepino[7,1-a]isoquinolin-5-one	IC50	220 nM	US-8853203: Diazepinone derivatives
9-cyclopropyl-2-(3-cyclopropyl-1,2,4-triazol-1-yl)-7,8-dihydro-4H-[1,4]diazepino[7,1-a]isoquinolin-5-one	IC50	226 nM	US-8853203: Diazepinone derivatives
CHEMBL2397341	IC50	257 nM
CHEMBL2397378	IC50	263 nM
9-cyclopropyl-10-fluoro-2-[4-(methoxymethyl)imidazol-1-yl]-7,8-dihydro-4H-[1,4]diazepino[7,1-a]isoquinolin-5-one	IC50	289 nM	US-8853203: Diazepinone derivatives
CHEMBL2397344	IC50	347 nM
CHEMBL2397346	IC50	398 nM
2-(4-cyclopropylimidazol-1-yl)-9-(6-fluoropyrazin-2-yl)-7,8-dihydro-4H-[1,4]diazepino[7,1-a]isoquinolin-5-one	IC50	402 nM	US-8853203: Diazepinone derivatives
CHEMBL2397342	IC50	417 nM
CHEMBL2418381	IC50	478 nM
2-[4-(methoxymethyl)imidazol-1-yl]-9-prop-1-en-2-yl-7,8-dihydro-4H-[1,4]diazepino[7,1-a]isoquinolin-5-one	IC50	490 nM	US-8853203: Diazepinone derivatives
9-cyclopropyl-2-(3-methoxy-1,2,4-triazol-1-yl)-7,8-dihydro-4H-[1,4]diazepino[7,1-a]isoquinolin-5-one	IC50	511 nM	US-8853203: Diazepinone derivatives
9-cyclopropyl-2-(4-methoxyimidazol-1-yl)-7,8-dihydro-4H-[1,4]diazepino[7,1-a]isoquinolin-5-one	IC50	511 nM	US-9650377: Diazepinone derivatives
10-chloro-9-methoxy-2-(3-methoxyphenyl)-7,8-dihydro-4H-[1,4]diazepino[7,1-a]isoquinolin-5-one	IC50	530 nM	US-8853203: Diazepinone derivatives
9-cyclopropyl-2-[4-(methoxymethyl)imidazol-1-yl]-7,8-dihydro-4H-[1,4]diazepino[7,1-a]isoquinolin-5-one	IC50	540 nM	US-8853203: Diazepinone derivatives
CHEMBL2418356	IC50	553 nM
2-(4-cyclopropylimidazol-1-yl)-9-(1,2-oxazol-5-yl)-7,8-dihydro-4H-[1,4]diazepino[7,1-a]isoquinolin-5-one	IC50	560 nM	US-8853203: Diazepinone derivatives
9-cyclopropyl-11-fluoro-2-[4-(methoxymethyl)imidazol-1-yl]-7,8-dihydro-4H-[1,4]diazepino[7,1-a]isoquinolin-5-one	IC50	561 nM	US-8853203: Diazepinone derivatives
CHEMBL2397368	IC50	603 nM
9-cyclobutyl-2-(3-methyl-1,2,4-triazol-1-yl)-7,8-dihydro-4H-[1,4]diazepino[7,1-a]isoquinolin-5-one	IC50	636 nM	US-8853203: Diazepinone derivatives
9-ethyl-2-(4-propan-2-ylimidazol-1-yl)-7,8-dihydro-4H-[1,4]diazepino[7,1-a]isoquinolin-5-one	IC50	650 nM	US-8853203: Diazepinone derivatives
9-iodo-2-(4-propan-2-ylimidazol-1-yl)-7,8-dihydro-4H-[1,4]diazepino[7,1-a]isoquinolin-5-one	IC50	650 nM	US-9650377: Diazepinone derivatives
9-acetyl-2-(4-cyclobutylimidazol-1-yl)-7,8-dihydro-4H-[1,4]diazepino[7,1-a]isoquinolin-5-one	IC50	660 nM	US-8853203: Diazepinone derivatives
CHEMBL2418379	IC50	669 nM
9-cyclopropyl-2-[4-(fluoromethyl)imidazol-1-yl]-7,8-dihydro-4H-[1,4]diazepino[7,1-a]isoquinolin-5-one	IC50	672 nM	US-8853203: Diazepinone derivatives
9-cyclopropyl-12-fluoro-2-[4-(methoxymethyl)imidazol-1-yl]-7,8-dihydro-4H-[1,4]diazepino[7,1-a]isoquinolin-5-one	IC50	687 nM	US-8853203: Diazepinone derivatives
9-methoxy-2-(1-methylpyrazol-3-yl)-7,8-dihydro-4H-[1,4]diazepino[7,1-a]isoquinolin-5-one	IC50	690 nM	US-8853203: Diazepinone derivatives
2Me4CPG	KI	700 nM
9-cyclopropyl-2-[4-(difluoromethyl)imidazol-1-yl]-7,8-dihydro-4H-[1,4]diazepino[7,1-a]isoquinolin-5-one	IC50	702 nM	US-8853203: Diazepinone derivatives
CHEMBL2397372	IC50	708 nM

ChEMBL bioactivities

1061 potent at pChembl≥5 of 1121 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
9.47	Ki	0.34	nM	CHEMBL174588
9.40	IC50	0.4	nM	CHEMBL238077
9.40	Ki	0.4	nM	CHEMBL1645349
9.40	IC50	0.4	nM	CHEMBL1951661
9.26	IC50	0.55	nM	CHEMBL174588
9.25	IC50	0.56	nM	CHEMBL178690
9.15	IC50	0.7	nM	CHEMBL393705
9.10	IC50	0.8	nM	CHEMBL1951872
9.06	Ki	0.87	nM	CHEMBL1645348
9.05	IC50	0.9	nM	CHEMBL1783874
9.00	IC50	1	nM	CHEMBL2205923
9.00	IC50	1	nM	CHEMBL2205922
9.00	IC50	1	nM	CHEMBL2205921
9.00	IC50	1	nM	CHEMBL2112967
9.00	IC50	1	nM	CHEMBL225032
8.96	IC50	1.1	nM	CHEMBL1783864
8.92	IC50	1.21	nM	CHEMBL174588
8.85	IC50	1.4	nM	CHEMBL241327
8.82	IC50	1.5	nM	CHEMBL1783875
8.74	IC50	1.8	nM	CHEMBL569270
8.74	IC50	1.8	nM	CHEMBL1784049
8.72	IC50	1.9	nM	CHEMBL1784053
8.70	IC50	2	nM	CHEMBL2205920
8.70	IC50	2	nM	CHEMBL175463
8.70	Ki	2	nM	CHEMBL1645350
8.70	IC50	2	nM	CHEMBL1783858
8.70	IC50	2	nM	CHEMBL1951690
8.70	IC50	2	nM	CHEMBL1951881
8.68	IC50	2.1	nM	CHEMBL1093560
8.68	IC50	2.1	nM	CHEMBL1783876
8.66	IC50	2.2	nM	CHEMBL236180
8.66	IC50	2.2	nM	CHEMBL235975
8.64	IC50	2.3	nM	CHEMBL1951882
8.62	IC50	2.4	nM	CHEMBL236177
8.62	IC50	2.4	nM	CHEMBL577729
8.60	IC50	2.5	nM	CHEMBL393922
8.59	IC50	2.6	nM	CHEMBL452618
8.59	IC50	2.6	nM	CHEMBL565943
8.54	IC50	2.9	nM	CHEMBL236994
8.52	IC50	3	nM	CHEMBL2205371
8.52	IC50	3	nM	CHEMBL2205909
8.52	IC50	3	nM	CHEMBL176279
8.52	IC50	3	nM	CHEMBL385336
8.52	IC50	3	nM	CHEMBL469382
8.52	IC50	3	nM	CHEMBL1784067
8.52	IC50	3	nM	CHEMBL1951879
8.51	IC50	3.1	nM	CHEMBL1093869
8.51	IC50	3.1	nM	CHEMBL1951669
8.48	IC50	3.3	nM	CHEMBL577833
8.47	IC50	3.4	nM	CHEMBL1951688

PubChem BioAssay actives

879 with measured affinity, of 2068 total; 50 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
3,4-dihydro-2H-pyrano[2,3-b]quinolin-7-yl-(4-methoxycyclohexyl)methanone	549905: Binding affinity to mGluR1	ki	0.0003	uM
5-(4-chlorophenyl)-13-(dimethylamino)-8-thia-5,10-diazatricyclo[7.4.0.02,7]trideca-1(13),2(7),3,9,11-pentaen-6-one	645618: Antagonist activity at human metabotropic glutamate receptor 1	ic50	0.0004	uM
13-(4-chlorophenyl)-10-thia-3,8,13,15-tetrazatetracyclo[7.7.0.02,6.011,16]hexadeca-1,4,6,8,11(16),14-hexaen-12-one	302748: Antagonist activity at human mGluR1a expressed in CHO cells assessed by measuring intracellular calcium by FLIPR assay	ic50	0.0004	uM
5-[1-(2-(18F)fluoro-3-pyridinyl)-5-methyltriazol-4-yl]-2-propyl-3H-isoindol-1-one	549905: Binding affinity to mGluR1	ki	0.0004	uM
2,3-dihydro-1H-cyclopenta[b]quinolin-7-yl-(4-methoxycyclohexyl)methanone	241789: Inhibitory concentration against human metabotropic glutamate receptor	ic50	0.0006	uM
13-(4-methylphenyl)-10-thia-3,8,13,15-tetrazatetracyclo[7.7.0.02,6.011,16]hexadeca-1,4,6,8,11(16),14-hexaen-12-one	302748: Antagonist activity at human mGluR1a expressed in CHO cells assessed by measuring intracellular calcium by FLIPR assay	ic50	0.0007	uM
5-(4-bromophenyl)-13-(methylamino)-8-thia-5,10-diazatricyclo[7.4.0.02,7]trideca-1(13),2(7),3,9,11-pentaen-6-one	645618: Antagonist activity at human metabotropic glutamate receptor 1	ic50	0.0008	uM
5-(4-chlorophenyl)-13-(prop-2-ynylamino)-8-thia-3,5,10-triazatricyclo[7.4.0.02,7]trideca-1(13),2(7),3,9,11-pentaen-6-one	599762: Antagonist activity at human mGluR1	ic50	0.0009	uM
(3-ethyl-2-(111C)methylquinolin-6-yl)-(4-methoxycyclohexyl)methanone	549905: Binding affinity to mGluR1	ki	0.0009	uM
(2-amino-3-ethylquinolin-6-yl)-(4-methoxycyclohexyl)methanone	241789: Inhibitory concentration against human metabotropic glutamate receptor	ic50	0.0010	uM
5-cycloheptyl-13-(dimethylamino)-8-thia-3,5,10-triazatricyclo[7.4.0.02,7]trideca-1(13),2(7),3,9,11-pentaen-6-one	282965: Antagonist activity at human mGluR1 expressed in 1321N1 cells assessed as effect on L-glutamate-induced calcium mobilization	ic50	0.0010	uM
5-(4-bromophenyl)-13-(dimethylamino)-8-thia-3,5,10,12-tetrazatricyclo[7.4.0.02,7]trideca-1(13),2(7),3,9,11-pentaen-6-one	717243: Antagonist activity at human mGluR1	ic50	0.0010	uM
5-(4-chlorophenyl)-13-(dimethylamino)-8-thia-3,5,10,12-tetrazatricyclo[7.4.0.02,7]trideca-1(13),2(7),3,9,11-pentaen-6-one	717243: Antagonist activity at human mGluR1	ic50	0.0010	uM
13-(dimethylamino)-5-(4-methylphenyl)-8-thia-3,5,10,12-tetrazatricyclo[7.4.0.02,7]trideca-1(13),2(7),3,9,11-pentaen-6-one	717243: Antagonist activity at human mGluR1	ic50	0.0010	uM
5-(4-chlorophenyl)-13-[methyl(prop-2-enyl)amino]-8-thia-3,5,10-triazatricyclo[7.4.0.02,7]trideca-1(13),2(7),3,9,11-pentaen-6-one	599762: Antagonist activity at human mGluR1	ic50	0.0011	uM
(5R)-14-(4-chlorophenyl)-5-methyl-6-oxa-11-thia-3,9,14,16-tetrazatetracyclo[8.7.0.02,7.012,17]heptadeca-1,7,9,12(17),15-pentaen-13-one	302748: Antagonist activity at human mGluR1a expressed in CHO cells assessed by measuring intracellular calcium by FLIPR assay	ic50	0.0014	uM
5-(4-methylphenyl)-13-(prop-2-ynylamino)-8-thia-3,5,10-triazatricyclo[7.4.0.02,7]trideca-1(13),2(7),3,9,11-pentaen-6-one	599762: Antagonist activity at human mGluR1	ic50	0.0015	uM
4-fluoro-N-methyl-N-[4-[6-(methylamino)pyrimidin-4-yl]-1,3-thiazol-2-yl]benzamide	449312: Antagonist activity at human mGluR1 receptor expressed in CHO cells by FLIPR assay	ic50	0.0018	uM
5-(4-bromophenyl)-13-(prop-2-ynylamino)-8-thia-3,5,10-triazatricyclo[7.4.0.02,7]trideca-1(13),2(7),3,9,11-pentaen-6-one	599762: Antagonist activity at human mGluR1	ic50	0.0018	uM
5-(4-bromophenyl)-13-[methyl(prop-2-ynyl)amino]-8-thia-3,5,10-triazatricyclo[7.4.0.02,7]trideca-1(13),2(7),3,9,11-pentaen-6-one	599762: Antagonist activity at human mGluR1	ic50	0.0019	uM
2,3-dihydrothieno[2,3-b]quinolin-6-yl-(4-methoxycyclohexyl)methanone	241789: Inhibitory concentration against human metabotropic glutamate receptor	ic50	0.0020	uM
5-(4-chlorophenyl)-13-(methylamino)-8-thia-5,10-diazatricyclo[7.4.0.02,7]trideca-1(13),2(7),3,9,11-pentaen-6-one	645618: Antagonist activity at human metabotropic glutamate receptor 1	ic50	0.0020	uM
5-(4-bromophenyl)-13-(ethylamino)-8-thia-5,10-diazatricyclo[7.4.0.02,7]trideca-1(13),2(7),3,9,11-pentaen-6-one	645618: Antagonist activity at human metabotropic glutamate receptor 1	ic50	0.0020	uM
5-(4-methoxyphenyl)-13-(prop-2-enylamino)-8-thia-3,5,10-triazatricyclo[7.4.0.02,7]trideca-1(13),2(7),3,9,11-pentaen-6-one	599762: Antagonist activity at human mGluR1	ic50	0.0020	uM
4-[1-(2-(18F)fluoro-3-pyridinyl)-5-methyltriazol-4-yl]-N-methyl-N-propan-2-yl-3,6-dihydro-2H-pyridine-1-carboxamide	594361: Binding affinity to mGluR1 by PET analysis	ki	0.0020	uM
13-(dimethylamino)-5-(4-methoxyphenyl)-8-thia-3,5,10,12-tetrazatricyclo[7.4.0.02,7]trideca-1(13),2(7),3,9,11-pentaen-6-one	717243: Antagonist activity at human mGluR1	ic50	0.0020	uM
5-(4-methoxyphenyl)-13-(prop-2-ynylamino)-8-thia-3,5,10-triazatricyclo[7.4.0.02,7]trideca-1(13),2(7),3,9,11-pentaen-6-one	599762: Antagonist activity at human mGluR1	ic50	0.0021	uM
11,13-diamino-5-(4-methylphenyl)-8-thia-3,5,10,12-tetrazatricyclo[7.4.0.02,7]trideca-1(13),2(7),3,9,11-pentaen-6-one	474914: Antagonist activity at human mGluR1	ic50	0.0021	uM
(5S)-14-(4-chlorophenyl)-5-methyl-6-oxa-11-thia-3,9,14,16-tetrazatetracyclo[8.7.0.02,7.012,17]heptadeca-1,7,9,12(17),15-pentaen-13-one	302748: Antagonist activity at human mGluR1a expressed in CHO cells assessed by measuring intracellular calcium by FLIPR assay	ic50	0.0022	uM
14-(4-methylphenyl)-6-oxa-11-thia-3,9,14,16-tetrazatetracyclo[8.7.0.02,7.012,17]heptadeca-1,7,9,12(17),15-pentaen-13-one	302748: Antagonist activity at human mGluR1a expressed in CHO cells assessed by measuring intracellular calcium by FLIPR assay	ic50	0.0022	uM
5-(4-bromophenyl)-13-(cyclopropylamino)-8-thia-5,10-diazatricyclo[7.4.0.02,7]trideca-1(13),2(7),3,9,11-pentaen-6-one	645618: Antagonist activity at human metabotropic glutamate receptor 1	ic50	0.0023	uM
N-[4-(6-aminopyrimidin-4-yl)-1,3-thiazol-2-yl]-4-fluoro-N-methylbenzamide	449312: Antagonist activity at human mGluR1 receptor expressed in CHO cells by FLIPR assay	ic50	0.0024	uM
(5R)-14-(4-methoxyphenyl)-5-methyl-6-oxa-11-thia-3,9,14,16-tetrazatetracyclo[8.7.0.02,7.012,17]heptadeca-1,7,9,12(17),15-pentaen-13-one	302748: Antagonist activity at human mGluR1a expressed in CHO cells assessed by measuring intracellular calcium by FLIPR assay	ic50	0.0024	uM
14-(4-methoxyphenyl)-6-oxa-11-thia-3,9,14,16-tetrazatetracyclo[8.7.0.02,7.012,17]heptadeca-1,7,9,12(17),15-pentaen-13-one	302748: Antagonist activity at human mGluR1a expressed in CHO cells assessed by measuring intracellular calcium by FLIPR assay	ic50	0.0025	uM
tert-butyl 4-[1-(3-fluoro-2-pyridinyl)triazol-4-yl]-3,6-dihydro-2H-pyridine-1-carboxylate	389921: Antagonist activity at human mGluR1 expressed in CHO cells assessed as calcium flux by FLIPR assay	ic50	0.0026	uM
2-cyclopropyl-5-(5-methyl-1-pyridin-3-yltriazol-4-yl)-2,3-dihydroinden-1-one	446923: Antagonist activity at human mGluR1 receptor expressed in CHO cell membranes assessed as inhibition of L-glutamate-induced calcium mobilization by FLIPR	ic50	0.0026	uM
14-(4-chlorophenyl)-6-oxa-11-thia-3,9,14,16-tetrazatetracyclo[8.7.0.02,7.012,17]heptadeca-1,7,9,12(17),15-pentaen-13-one	302748: Antagonist activity at human mGluR1a expressed in CHO cells assessed by measuring intracellular calcium by FLIPR assay	ic50	0.0029	uM
(4-methoxycyclohexyl)-(2-propylquinolin-6-yl)methanone	241789: Inhibitory concentration against human metabotropic glutamate receptor	ic50	0.0030	uM
13-(dimethylamino)-5-(4-ethylphenyl)-8-thia-3,5,10-triazatricyclo[7.4.0.02,7]trideca-1(13),2(7),3,9,11-pentaen-6-one	271536: Antagonist activity at human mGluR1 expressed in 1321N1 cells	ic50	0.0030	uM
2-[2-[[4-(2,3-dihydro-1H-inden-2-ylamino)pyrido[3,4-d]pyrimidin-6-yl]amino]ethoxy]ethanol	353566: Antagonist activity at mGluR1	ic50	0.0030	uM
5-(4-chlorophenyl)-13-(ethylamino)-8-thia-5,10-diazatricyclo[7.4.0.02,7]trideca-1(13),2(7),3,9,11-pentaen-6-one	645618: Antagonist activity at human metabotropic glutamate receptor 1	ic50	0.0030	uM
5-(4-chlorophenyl)-13-(prop-2-ynylamino)-8-thia-3,5,10,12-tetrazatricyclo[7.4.0.02,7]trideca-1(13),2(7),3,9,11-pentaen-6-one	599762: Antagonist activity at human mGluR1	ic50	0.0030	uM
13-[ethyl(methyl)amino]-5-(4-methoxyphenyl)-8-thia-3,5,10,12-tetrazatricyclo[7.4.0.02,7]trideca-1(13),2(7),3,9,11-pentaen-6-one	717243: Antagonist activity at human mGluR1	ic50	0.0030	uM
5-(4-chlorophenyl)-13-(cyclopropylamino)-8-thia-3,5,10,12-tetrazatricyclo[7.4.0.02,7]trideca-1(13),2(7),3,9,11-pentaen-6-one	717243: Antagonist activity at human mGluR1	ic50	0.0030	uM
5-(1,3-benzothiazol-6-yl)-13-(dimethylamino)-8-thia-5,10-diazatricyclo[7.4.0.02,7]trideca-1(13),2(7),3,9,11-pentaen-6-one	645618: Antagonist activity at human metabotropic glutamate receptor 1	ic50	0.0031	uM
13-amino-5-(4-methylphenyl)-11-sulfanylidene-8-thia-3,5,10,12-tetrazatricyclo[7.4.0.02,7]trideca-1(13),2(7),3,9-tetraen-6-one	474914: Antagonist activity at human mGluR1	ic50	0.0031	uM
2-ethyl-5-[1-(2-fluoro-3-pyridinyl)-5-methyltriazol-4-yl]-3H-isoindol-1-one	446923: Antagonist activity at human mGluR1 receptor expressed in CHO cell membranes assessed as inhibition of L-glutamate-induced calcium mobilization by FLIPR	ic50	0.0033	uM
13-(methylamino)-5-(4-methylphenyl)-8-thia-5,10-diazatricyclo[7.4.0.02,7]trideca-1(13),2(7),3,9,11-pentaen-6-one	645618: Antagonist activity at human metabotropic glutamate receptor 1	ic50	0.0034	uM
2-cyclopropyl-5-[1-(2-fluoro-3-pyridinyl)-5-methyltriazol-4-yl]-3H-isoindol-1-one	446923: Antagonist activity at human mGluR1 receptor expressed in CHO cell membranes assessed as inhibition of L-glutamate-induced calcium mobilization by FLIPR	ic50	0.0035	uM
6-[1-(2-fluoro-3-pyridinyl)-5-methyltriazol-4-yl]quinoline	549904: Binding affinity to human mGluR1	ic50	0.0036	uM

CTD chemical–gene interactions

18 total (human), top 18 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	increases expression	2
Aflatoxin B1	decreases methylation, increases methylation	2
ethylbenzene	affects cotreatment, decreases expression	1
arsenite	increases methylation	1
sodium arsenite	increases expression	1
S-(1,2-dichlorovinyl)cysteine	increases expression, affects response to substance	1
CGP 52608	affects binding, increases reaction	1
bisphenol S	decreases methylation	1
Vorinostat	decreases expression	1
Benzo(a)pyrene	affects methylation, decreases methylation, increases methylation	1
Doxorubicin	decreases expression	1
Lipopolysaccharides	affects response to substance, increases expression	1
Tobacco Smoke Pollution	increases expression	1
Toluene	affects cotreatment, decreases expression	1
Xylenes	affects cotreatment, decreases expression	1
Zinc	decreases expression	1
1-Butanol	affects localization, affects reaction	1
Acrylamide	increases expression	1

ChEMBL screening assays

284 unique, capped per target: 177 functional, 107 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1004112	Functional	Antagonist activity at cloned mGluR1 expressed in CHO cells co-transfected with chimeric G protein Gqi9 assessed as inhibition of glutamate-induced intracellular inositol phosphate accumulation at 10 uM by phosphoinositide hydrolysis assay	Structure-activity relationships comparing N-(6-methylpyridin-yl)-substituted aryl amides to 2-methyl-6-(substituted-arylethynyl)pyridines or 2-methyl-4-(substituted-arylethynyl)thiazoles as novel metabotropic glutamate receptor subtype 5 antagonists. — J Med Chem
CHEMBL1018991	Binding	Displacement of [3H]Quisqualate from human mGluR1A receptor expressed in BHK cells	Design, synthesis and biological evaluation of novel bicyclo[1.1.1]pentane-based omega-acidic amino acids as glutamate receptors ligands. — Bioorg Med Chem

Cellosaurus cell lines

6 cell lines: 5 cancer cell line, 1 transformed cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_0237	Capan-1	Cancer cell line	Male
CVCL_0A59	Capan1M9	Cancer cell line	Male
CVCL_D1SZ	Abcam U-87MG GRM1 KO	Cancer cell line	Male
CVCL_E4I0	CHO SSF3VN9hmGluR1b	Transformed cell line	Female
CVCL_KU68	U2OS GRM1 Gq	Cancer cell line	Female
CVCL_S022	Capan-1 SimpleCell O-GalNAc	Cancer cell line	Male

Clinical trials (associated diseases)

299 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT00950196	PHASE4	COMPLETED	Amantadine for Improving Neurologic Symptoms in Ataxia-Telangiectasia
NCT04107740	PHASE4	COMPLETED	C-Trelin Orally Disintegrated(OD) Tablet 5mg in Ataxia Due to Spinocerebellar Degeneration
NCT05657860	PHASE4	COMPLETED	Guanfacine Extended Release for the Reduction of Aggression and Self-injurious Behavior Associated With Prader-Willi Syndrome
NCT05744479	PHASE4	RECRUITING	Metformin for Antipsychotic-induced Weight Gain in Adults With Intellectual Disability
NCT06107829	PHASE4	WITHDRAWN	Valbenazine Treatment of Tardive Dyskinesia in Adults With Intellectual/Developmental Disabilities
NCT06997198	PHASE4	NOT_YET_RECRUITING	Deutetrabenazine Treatment for Tardive Dyskinesia in Intellectual/Developmental Disabilities
NCT01970098	PHASE3	COMPLETED	A Confirmatory Study of KPS-0373 in Patients With Spinocerebellar Degeneration (SCD)
NCT01970111	PHASE3	COMPLETED	An Extension Study of KPS-0373 in Patients With Spinocerebellar Degeneration (SCD)
NCT01970124	PHASE3	COMPLETED	A Long-Term Study of KPS-0373 in Patients With Spinocerebellar Degeneration (SCD)
NCT01970137	PHASE3	COMPLETED	A 24-week Open-label Study of KPS-0373 in Patients With Spinocerebellar Degeneration (SCD)
NCT02889302	PHASE3	COMPLETED	An Additional Confirmatory Study of KPS-0373 in Patients With Spinocerebellar Degeneration (SCD)
NCT03408080	PHASE3	ACTIVE_NOT_RECRUITING	Open Pilot Trial of BHV-4157
NCT03701399	PHASE3	ACTIVE_NOT_RECRUITING	Troriluzole in Adult Participants With Spinocerebellar Ataxia
NCT03901638	PHASE3	TERMINATED	Tllsh2910 for Ataxia and Gut Microbiota Alteration in Patients of Multiple System Atrophy
NCT07040137	PHASE3	RECRUITING	Confirmatory Study 3 of KPS-0373 in Patients With Spinocerebellar Degeneration
NCT02270736	PHASE3	COMPLETED	Clinical Study to Investigate the Efficacy and Safety of NT 201 Compared to Placebo in the Treatment of Chronic Troublesome Drooling Associated With Neurological Disorders and/or Intellectual Disability
NCT00034242	PHASE2	COMPLETED	High-Dose Intravenous Immunoglobulin to Treat Cerebellar Degeneration
NCT00202397	PHASE2	COMPLETED	Effect of Riluzole as a Symptomatic Approach in Patients With Chronic Cerebellar Ataxia
NCT00863538	PHASE2	COMPLETED	Phase II Study of KPS-0373 in Patients With Spinocerebellar Degeneration (SCD)
NCT01004016	PHASE2	COMPLETED	A Study of KPS-0373 in Patients With Spinocerebellar Degeneration (SCD)
NCT01350440	PHASE2	COMPLETED	Safety and Efficacy of Intravenous Immune Globulin in Treating Spinocerebellar Ataxia
NCT02540655	PHASE2	COMPLETED	Efficacy and Safety Study of Stemchymal® in Polyglutamine Spinocerebellar Ataxia
NCT03932669	PHASE2	COMPLETED	Effect of Nilotinib in Cerebellar Ataxia Patients
NCT04301284	PHASE2	WITHDRAWN	Study of CAD-1883 for Spinocerebellar Ataxia
NCT05125666	PHASE2	UNKNOWN	Efficacy of Dual Task Training on Children With Ataxia After Medulloblastoma Resection
NCT06397274	PHASE2	NOT_YET_RECRUITING	Stemchymal® for Polyglutamine Spinocerebellar Ataxia
NCT02304302	PHASE2	COMPLETED	Down Syndrome Memantine Follow-up Study
NCT03862950	PHASE2	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome (Met)
NCT04529226	PHASE2	UNKNOWN	Study to Compare Clozapine vs Treatment as Usual in People With Intellectual Disability & Treatment-resistant Psychosis
NCT04821856	PHASE2	COMPLETED	Evaluation of the Effectiveness of Cannabidiol in Treating Severe Behavioural Problems in Children and Adolescents With Intellectual Disability
NCT00683943	PHASE1	COMPLETED	Lithium Treatment for Patients With Spinocerebellar Ataxia Type I
NCT02287064	PHASE1	UNKNOWN	An Open-label Trial of Intravenous Immune Globulin (IVIG)in Treating Spinocerebellar Ataxias
NCT05157802	PHASE1	ACTIVE_NOT_RECRUITING	Promoting Physical Activity Engagement for People With Early-stage Cerebellar Ataxia
NCT05273320	PHASE1	COMPLETED	Clinical Trial of Nabilone for Aggression in Adults With Intellectual and Developmental Disabilities
NCT05301361	PHASE1	ENROLLING_BY_INVITATION	Sensitivity of the NIH Toolbox to Stimulant Treatment in Intellectual Disabilities
NCT06016764	PHASE1	COMPLETED	Use of MRI and cTBS for Catatonia in Autism
NCT06586827	PHASE1	COMPLETED	Impact of Competency-Based Training and Technical Assistance Employment Outcomes of Individuals With ID/DD
NCT07531940	PHASE1	NOT_YET_RECRUITING	Escalating Doses of Memantine in Down Syndrome (MEDS-123)
NCT01104649	PHASE2/PHASE3	COMPLETED	Efficacy of Riluzole in Hereditary Cerebellar Ataxia
NCT02960893	PHASE2/PHASE3	COMPLETED	Trial in Adult Participants With Spinocerebellar Ataxia (SCA)