GLRB

Summary

GLRB (glycine receptor beta, HGNC:4329) is a protein-coding gene on chromosome 4q32.1, encoding Glycine receptor subunit beta (P48167). Subunit of heteromeric glycine-gated chloride channels.

This gene encodes the beta subunit of the glycine receptor, which is a pentamer composed of alpha and beta subunits. The receptor functions as a neurotransmitter-gated ion channel, which produces hyperpolarization via increased chloride conductance due to the binding of glycine to the receptor. Mutations in this gene cause startle disease, also known as hereditary hyperekplexia or congenital stiff-person syndrome, a disease characterized by muscular rigidity. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 2743 — RefSeq curated summary.

At a glance

• Gene–disease (curated): hyperekplexia 2 (Definitive, GenCC) — +1 more curated relationship
• GWAS associations: 2
• Clinical variants (ClinVar): 463 total — 17 pathogenic, 5 likely-pathogenic
• Phenotypes (HPO): 31
• Druggable target: yes
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity no evidence
• MANE Select transcript: NM_000824

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:4329
Approved symbol	GLRB
Name	glycine receptor beta
Location	4q32.1
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000109738
Ensembl biotype	protein_coding
OMIM	138492
Entrez	2743

Gene structure

Transcript identifiers

Ensembl transcripts: 16 — 13 protein_coding, 2 nonsense_mediated_decay, 1 retained_intron

ENST00000264428, ENST00000506411, ENST00000509282, ENST00000510970, ENST00000512619, ENST00000515642, ENST00000541722, ENST00000874195, ENST00000874196, ENST00000960007, ENST00000960008, ENST00000960009, ENST00000960010, ENST00000960011, ENST00000960012, ENST00000960013

RefSeq mRNA: 3 — MANE Select: NM_000824 NM_000824, NM_001166060, NM_001166061

CCDS: CCDS3796, CCDS54813

Canonical transcript exons

ENST00000264428 — 10 exons

Exon	Start	End
ENSE00000740246	157138809	157138949
ENSE00000740252	157143807	157143959
ENSE00000740254	157152718	157153010
ENSE00000813569	157077996	157078146
ENSE00002021448	157076150	157076297
ENSE00003506646	157170432	157172090
ENSE00003560964	157136469	157136698
ENSE00003605009	157136804	157136886
ENSE00003667917	157120556	157120662
ENSE00003687462	157122330	157122397

Expression profiles

Bgee: expression breadth ubiquitous, 236 present calls, max score 98.75.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 11.6660 / max 274.0311, expressed in 1159 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
50240	11.3905	1154
50239	0.2195	101
203396	0.0560	18

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
frontal pole	UBERON:0002795	98.75	gold quality
Brodmann (1909) area 10	UBERON:0013541	98.54	gold quality
middle frontal gyrus	UBERON:0002702	96.70	gold quality
lateral nuclear group of thalamus	UBERON:0002736	95.80	gold quality
pons	UBERON:0000988	95.55	gold quality
paraflocculus	UBERON:0005351	95.21	gold quality
prefrontal cortex	UBERON:0000451	94.35	gold quality
Brodmann (1909) area 23	UBERON:0013554	93.93	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	93.51	gold quality
endothelial cell	CL:0000115	93.43	gold quality
primary visual cortex	UBERON:0002436	93.42	gold quality
Brodmann (1909) area 9	UBERON:0013540	93.29	gold quality
superior frontal gyrus	UBERON:0002661	92.89	gold quality
frontal cortex	UBERON:0001870	92.67	gold quality
occipital lobe	UBERON:0002021	92.55	gold quality
postcentral gyrus	UBERON:0002581	92.37	gold quality
parietal lobe	UBERON:0001872	92.12	gold quality
neocortex	UBERON:0001950	92.09	gold quality
superior vestibular nucleus	UBERON:0007227	91.50	gold quality
orbitofrontal cortex	UBERON:0004167	91.42	gold quality
cerebral cortex	UBERON:0000956	91.40	gold quality
cingulate cortex	UBERON:0003027	90.61	gold quality
anterior cingulate cortex	UBERON:0009835	90.58	gold quality
substantia nigra pars compacta	UBERON:0001965	90.38	gold quality
telencephalon	UBERON:0001893	89.86	gold quality
cortical plate	UBERON:0005343	89.56	gold quality
cerebellar vermis	UBERON:0004720	89.45	gold quality
Brodmann (1909) area 46	UBERON:0006483	89.38	gold quality
choroid plexus epithelium	UBERON:0003911	89.10	gold quality
middle temporal gyrus	UBERON:0002771	89.05	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	5.04

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

112 targeting GLRB, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-4476	100.00	68.18	2030
HSA-MIR-6876-5P	100.00	67.68	2126
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-4533	100.00	69.48	2758
HSA-MIR-4776-3P	100.00	68.73	1340
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-1252-5P	100.00	69.80	2774
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-568	99.98	69.86	2084
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-3065-5P	99.97	71.56	3281
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-548AT-5P	99.96	70.83	2666
HSA-MIR-3658	99.96	73.87	4379
HSA-LET-7C-3P	99.95	73.42	2862
HSA-MIR-3682-5P	99.93	67.97	1163
HSA-MIR-381-3P	99.93	71.87	2854
HSA-MIR-205-3P	99.92	69.92	3165
HSA-MIR-3119	99.92	71.34	2390
HSA-MIR-300	99.92	71.76	2856
HSA-MIR-1305	99.91	71.43	3443
HSA-MIR-10523-5P	99.91	69.22	2038
HSA-MIR-3671	99.90	73.04	3897

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 23)

• proton modulation of glycine receptor function is determined by extracellular domain in both the alpha1 and beta subunits (PMID:14563849)
• Stoichiometry of recombinant heteromeric glycine receptors revealed by a pore-lining region point mutation (PMID:14698963)
• Report interaction of androsterone and progesterone with inhibitory ligand-gated ion channels: a patch clamp study. (PMID:19705103)
• This study presents a large family with Hereditary hyperekplexia (HH) as a result of homozygous mutation in GLRB. (PMID:21391991)
• The authors have identified a protein kinase C (PKC) phosphorylation site within the cytoplasmic domain of the beta-subunit of the GlyR (residue S403) that causes a reduction of the binding affinity between the receptor and gephyrin. (PMID:21829170)
• Hereditary hyperekplexia-causing mutations that modify alpha1 beta GlyR channel function are almost exclusively located in the alpha1 to the exclusion of the beta subunit. (PMID:22132222)
• Distinct properties of glycine receptor beta+/alpha- interface: unambiguously characterizing heteromeric interface reconstituted in homomeric protein. (PMID:22535951)
• investigated neural progenitor cells in respect to their glycine receptor function and subunit expression using electrophysiology, calcium imaging, immunocytochemistry, and quantitative real-time PCR (PMID:22606311)
• We report novel GLRB mutations in hyperekplexia (PMID:23182654)
• This study describes the definitive assignment of GLRB as the third major gene for hyperekplexia and impacts on the genetic stratification and biological causation of this neonatal/paediatric disorder. (PMID:23184146)
• Systematic DNA sequencing of GLRB in individuals with hyperekplexia revealed new missense mutations in GLRB, resulting in M177R, L285R and W310C substitutions. (PMID:23238346)
• p.E375X truncated subunits are incorporated into functional hGlyRs together with unmutated alpha1 or alpha1 plus beta subunits. (PMID:24108130)
• The N-terminal region of GABRA3 and the GlyR beta subunit occupies the same binding site of gephyrin. (PMID:25531214)
• Whole-exome sequencing in ASD patients from each family identified a second rare inherited genetic variant, affecting GLRB expressed in inhibitory or in excitatory synapses. (PMID:26055424)
• GLRA1 and GLRB mutations are responsible for abnormal startled reactions in humans. (Review) (PMID:26845851)
• A genome-wide significant association was found between ACQ and single non-coding nucleotide variants of the GLRB gene (rs78726293, P = 3.3 x 10 - 8; rs191260602, P = 3.9 x 10- 8).GLRB gene expression was found to be modulated by rs7688285 in brain tissue, as well as cell culture. (PMID:28167838)
• GLRB variants are associated with etiopathogenesis of fear and anxiety disorders. (PMID:28872638)
• Using quantitative photoactivated localisation microscopy the authors found that alpha-1 and alpha-3 containing glycine receptors display the same alpha3:beta2 stoichiometry and gephyrin binding. (PMID:28883437)
• The association between the missense SNP rs2235371 in gene IRF6 and NSCL/P suggests that this SNP may play an important role as a risk factor for NSCL/P in the Han Chinese populations. (PMID:30462859)
• single nucleotide polymorphism of glrb interacts in a complex manner with Panic Disorder /AgoraphobiaG on a functional systems level and might be involved in the development of PD/AG but not in their treatment. (PMID:31444036)
• Clinical, genetic, and functional characterization of the glycine receptor beta-subunit A455P variant in a family affected by hyperekplexia syndrome. (PMID:35526563)
• Glycine Receptor beta-Targeting Autoantibodies Contribute to the Pathology of Autoimmune Diseases. (PMID:38215349)
• Gating mechanism of the human alpha1beta GlyR by glycine. (PMID:39146932)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	glrbb	ENSDARG00000052769
danio_rerio	glrba	ENSDARG00000052782
mus_musculus	Glrb	ENSMUSG00000028020
rattus_norvegicus	Glrb	ENSRNOG00000010199

Paralogs (45): GABRA3 (ENSG00000011677), GABRA1 (ENSG00000022355), CHRNA3 (ENSG00000080644), GABRP (ENSG00000094755), CHRNA4 (ENSG00000101204), GLRA2 (ENSG00000101958), GABRE (ENSG00000102287), CHRNE (ENSG00000108556), GABRA4 (ENSG00000109158), GABRR2 (ENSG00000111886), GABRG2 (ENSG00000113327), CHRNB4 (ENSG00000117971), CHRNA2 (ENSG00000120903), CHRNA10 (ENSG00000129749), CHRND (ENSG00000135902), CHRNA1 (ENSG00000138435), GLRA3 (ENSG00000145451), GABRA6 (ENSG00000145863), GABRB2 (ENSG00000145864), GLRA1 (ENSG00000145888), GABRR1 (ENSG00000146276), CHRNB3 (ENSG00000147432), CHRNA6 (ENSG00000147434), HTR3B (ENSG00000149305), GABRA2 (ENSG00000151834), CHRNB2 (ENSG00000160716), GABRG1 (ENSG00000163285), GABRB1 (ENSG00000163288), GABRB3 (ENSG00000166206), CHRFAM7A (ENSG00000166664), HTR3A (ENSG00000166736), CHRNA5 (ENSG00000169684), CHRNB1 (ENSG00000170175), CHRNA9 (ENSG00000174343), CHRNA7 (ENSG00000175344), HTR3C (ENSG00000178084), GABRG3 (ENSG00000182256), GABRR3 (ENSG00000183185), HTR3E (ENSG00000186038), HTR3D (ENSG00000186090)

Protein

Protein identifiers

Glycine receptor subunit beta — P48167 (reviewed: P48167)

Alternative names: Glycine receptor 58 kDa subunit

All UniProt accessions (3): P48167, D6R9Y9, D6RD86

UniProt curated annotations — full annotation on UniProt →

Function. Subunit of heteromeric glycine-gated chloride channels. Plays an important role in the down-regulation of neuronal excitability. Contributes to the generation of inhibitory postsynaptic currents.

Subunit / interactions. Forms heteropentamers with glycin receptor alpha subunits. Heteropentamers with GLRA1 can be composed of two GLRA1 and three GLRB subunits, or three GLRA1 and two GLRB subunits, or four GLRA1 subunits and one GLRB subunit. Forms heteropentamers with GLRA2. Functional GLRB-GLRA2 heteropentamers contain four GLRA2 subunits and one GLRB subunit, although alternative subunit composition cannot be excluded. Forms a heteropentamer with GLRA3. Interacts with GPHN.

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

Disease relevance. Hyperekplexia 2 (HKPX2) [MIM:614619] A neurologic disorder characterized by muscular rigidity of central nervous system origin, particularly in the neonatal period, and by an exaggerated startle response to unexpected acoustic or tactile stimuli. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Channel opening is triggered by extracellular glycine. Heteropentameric channels composed of GLRB and GLRA1 are activated by lower glycine levels than homopentameric GLRA1.

Similarity. Belongs to the ligand-gated ion channel (TC 1.A.9) family. Glycine receptor (TC 1.A.9.3) subfamily. GLRB sub-subfamily.

Isoforms (2)

UniProt ID	Names	Canonical?
P48167-1	1	yes
P48167-2	2

RefSeq proteins (3): NP_000815, NP_001159532, NP_001159533 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR006029	Neurotrans-gated_channel_TM	Domain
IPR006201	Neur_channel	Family
IPR006202	Neur_chan_lig-bd	Domain
IPR008060	Glycine_rcpt_B	Family
IPR018000	Neurotransmitter_ion_chnl_CS	Conserved_site
IPR036719	Neuro-gated_channel_TM_sf	Homologous_superfamily
IPR036734	Neur_chan_lig-bd_sf	Homologous_superfamily
IPR038050	Neuro_actylchol_rec	Homologous_superfamily
IPR047029	GlyR_beta_TM	Domain
IPR047031	GlyR_beta__ECD	Domain

Pfam: PF02931, PF02932

Catalyzed reactions (Rhea), 1 shown:

• chloride(in) = chloride(out) (RHEA:29823)

UniProt features (28 total): sequence variant 5, topological domain 4, transmembrane region 4, binding site 3, glycosylation site 2, disulfide bond 2, splice variant 2, mutagenesis site 2, signal peptide 1, chain 1, site 1, modified residue 1

Structure

Experimental structures (PDB)

12 structures.

PDB	Method	Resolution (Å)
8DN3	ELECTRON MICROSCOPY	3.55
5BKF	ELECTRON MICROSCOPY	3.6
7KUY	ELECTRON MICROSCOPY	3.6
9BP7	ELECTRON MICROSCOPY	3.6
8DN5	ELECTRON MICROSCOPY	3.63
9BP0	ELECTRON MICROSCOPY	3.67
5BKG	ELECTRON MICROSCOPY	3.8
7L31	ELECTRON MICROSCOPY	3.8
9BOY	ELECTRON MICROSCOPY	3.81
9BOZ	ELECTRON MICROSCOPY	3.84
8DN2	ELECTRON MICROSCOPY	3.9
8DN4	ELECTRON MICROSCOPY	4.1

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P48167-F1	78.85	0.49

Functional residue map

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

Catalytic / active sites (1): 307 (important for obstruction of the ion pore in the closed conformation)

Ligand- & substrate-binding residues (3): 108; 174; 250

Post-translational modifications (1): 391

Disulfide bonds (2): 183–197, 243–255

Glycosylation sites (2): 54, 242

Mutagenesis-validated functional residues (2):

Position	Phenotype
54	prevents proper assembly of the glra2/glrb heteropentamer receptor.
242	loss of glycosylation. prevents proper assembly of the glra2/glrb heteropentamer receptor.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-112314	Neurotransmitter receptors and postsynaptic signal transmission

MSigDB gene sets: 286 (showing top): GCACCTT_MIR18A_MIR18B, GOBP_SINGLE_FERTILIZATION, chr4q32, MODULE_274, TSENG_IRS1_TARGETS_UP, GOBP_BEHAVIOR, GOBP_ADULT_BEHAVIOR, AAGCCAT_MIR135A_MIR135B, GOBP_INORGANIC_ANION_TRANSPORT, GOBP_ADULT_LOCOMOTORY_BEHAVIOR, ACEVEDO_LIVER_CANCER_WITH_H3K27ME3_UP, GOBP_REFLEX, SMID_BREAST_CANCER_RELAPSE_IN_LIVER_DN, GOBP_CELL_CELL_SIGNALING, MODULE_66

GO Biological Process (18): startle response (GO:0001964), monoatomic ion transport (GO:0006811), neuropeptide signaling pathway (GO:0007218), chemical synaptic transmission (GO:0007268), acrosome reaction (GO:0007340), nervous system development (GO:0007399), visual perception (GO:0007601), adult walking behavior (GO:0007628), synaptic transmission, glycinergic (GO:0060012), righting reflex (GO:0060013), gamma-aminobutyric acid receptor clustering (GO:0097112), chloride transmembrane transport (GO:1902476), chloride transport (GO:0006821), monoatomic ion transmembrane transport (GO:0034220), regulation of membrane potential (GO:0042391), neuromuscular process (GO:0050905), regulation of postsynaptic membrane potential (GO:0060078), excitatory postsynaptic potential (GO:0060079)

GO Molecular Function (11): transmembrane signaling receptor activity (GO:0004888), excitatory extracellular ligand-gated monoatomic ion channel activity (GO:0005231), glycine binding (GO:0016594), extracellularly glycine-gated ion channel activity (GO:0016933), extracellularly glycine-gated chloride channel activity (GO:0016934), protein-containing complex binding (GO:0044877), transmitter-gated monoatomic ion channel activity involved in regulation of postsynaptic membrane potential (GO:1904315), monoatomic ion channel activity (GO:0005216), extracellular ligand-gated monoatomic ion channel activity (GO:0005230), chloride channel activity (GO:0005254), protein binding (GO:0005515)

GO Cellular Component (12): cytoplasm (GO:0005737), plasma membrane (GO:0005886), glycine-gated chloride channel complex (GO:0016935), dendrite (GO:0030425), postsynaptic membrane (GO:0045211), glycinergic synapse (GO:0098690), GABA-ergic synapse (GO:0098982), postsynaptic specialization (GO:0099572), membrane (GO:0016020), chloride channel complex (GO:0034707), cell projection (GO:0042995), synapse (GO:0045202)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Transmission across Chemical Synapses	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
regulation of postsynaptic membrane potential	2
binding	2
postsynapse	2
synapse	2
response to external stimulus	1
neuromuscular process	1
transport	1
G protein-coupled receptor signaling pathway	1
anterograde trans-synaptic signaling	1
membrane fusion involved in acrosome reaction	1
single fertilization	1
reproductive process	1
acrosomal vesicle exocytosis	1
system development	1
sensory perception of light stimulus	1
adult locomotory behavior	1
walking behavior	1
chemical synaptic transmission	1
reflex	1
postsynaptic membrane organization	1
neurotransmitter-gated ion channel clustering	1
chloride transport	1
monoatomic anion transmembrane transport	1
monoatomic anion transport	1
inorganic anion transport	1
monoatomic ion transport	1
transmembrane transport	1
monoatomic ion transmembrane transport	1
regulation of biological quality	1
nervous system process	1
regulation of membrane potential	1
chemical synaptic transmission, postsynaptic	1
signaling receptor activity	1
extracellular ligand-gated monoatomic ion channel activity	1
excitatory postsynaptic potential	1
amino acid binding	1
carboxylic acid binding	1
cation binding	1
excitatory extracellular ligand-gated monoatomic ion channel activity	1

Protein interactions and networks

STRING

1270 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
GLRB	GPHN	Q9NQX3	959
GLRB	SLC6A5	Q9Y345	918
GLRB	ARHGEF9	O43307	900
GLRB	GARS1	P41250	663
GLRB	AMPH	P49418	648
GLRB	SLC6A2	P23975	626
GLRB	NPY5R	Q15761	582
GLRB	TRAK1	Q9UPV9	555
GLRB	BIN1	O00499	544
GLRB	NBEA	Q8NFP9	519
GLRB	GRIA2	P42262	513
GLRB	SLC32A1	Q9H598	487
GLRB	GAD2	Q05329	476
GLRB	NLGN4X	Q8N0W4	465
GLRB	EFHB	Q8N7U6	417

IntAct

55 interactions, top by confidence:

A	B	Type	Score
NEMP1	RGPD8	psi-mi:“MI:0914”(association)	0.640
TCTN2	TPST2	psi-mi:“MI:0914”(association)	0.530
GABRA3	HLA-C	psi-mi:“MI:0914”(association)	0.530
NRN1	SLC1A1	psi-mi:“MI:0914”(association)	0.530
CHRNA4	FZD6	psi-mi:“MI:0914”(association)	0.530
HDLBP	GLRB	psi-mi:“MI:0915”(physical association)	0.400
GLRA1	GLRB	psi-mi:“MI:0915”(physical association)	0.400
	HAX1	psi-mi:“MI:0914”(association)	0.350
CHRNA3	TMEM223	psi-mi:“MI:0914”(association)	0.350
CLEC2D	TMEM120B	psi-mi:“MI:0914”(association)	0.350
BTNL8	TMEM131L	psi-mi:“MI:0914”(association)	0.350
TMPRSS11B		psi-mi:“MI:0914”(association)	0.350
ASIC4	UPK3BL1	psi-mi:“MI:0914”(association)	0.350
GABRA3	GPAA1	psi-mi:“MI:0914”(association)	0.350
NRN1	ADGRL1	psi-mi:“MI:0914”(association)	0.350
GRIA3	SEMA4F	psi-mi:“MI:0914”(association)	0.350
TTYH1	TMEM223	psi-mi:“MI:0914”(association)	0.350
CHRNA4	TMEM223	psi-mi:“MI:0914”(association)	0.350
HTR3B	TMEM223	psi-mi:“MI:0914”(association)	0.350
CLRN2	FAM234B	psi-mi:“MI:0914”(association)	0.350
TCTN2	TMEM131L	psi-mi:“MI:0914”(association)	0.350
PSCA	METTL15	psi-mi:“MI:0914”(association)	0.350
KLRC1	METTL15	psi-mi:“MI:0914”(association)	0.350
SCN4A	C2CD4B	psi-mi:“MI:0914”(association)	0.350

BioGRID (57): GLRB (Affinity Capture-MS), GLRB (Reconstituted Complex), GLRB (Affinity Capture-MS), GLRB (Affinity Capture-MS), GLRB (Affinity Capture-MS), GLRB (Affinity Capture-MS), GLRB (Affinity Capture-MS), GLRB (Affinity Capture-MS), GLRB (Affinity Capture-MS), GLRB (Affinity Capture-MS), GLRB (Affinity Capture-MS), GLRB (Affinity Capture-MS), GLRB (Affinity Capture-RNA), HDLBP (Proximity Label-MS), GLRB (Proximity Label-MS)

ESM2 similar proteins: A0A1S4GYH6, A0A1S4H2E2, A8XF54, A8XNX8, D4AYW0, G5EBR3, G5ECT0, G5EDN0, G5EG88, H2L006, H2QAR6, O18276, O18965, O76554, O95259, P20781, P24612, P25123, P34271, P41849, P48167, P48168, P54244, P54245, P54246, Q02280, Q09274, Q09453, Q10025, Q17298, Q18812, Q21005, Q27394, Q5BKX6, Q60603, Q60NC0, Q63472, Q75NA5, Q86DA5, Q8NCM2

Diamond homologs: A0A1S4H2E2, A8MPY1, D1LYT2, G5EBR3, O14764, O75311, O93430, P0C2W5, P15431, P18505, P18506, P19019, P20781, P22771, P22933, P23416, P24045, P25123, P28472, P47870, P48167, P48168, P63079, P63080, P63137, P63138, Q08832, Q61603, Q75NA5, Q7TNC8, Q94900, Q9BLY8, Q9GJS9, Q9V9Y4, F1R8P4, O00591, O09028, O18276, P07727, P08219

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
SRC	up-regulates	GLRB	phosphorylation
glycine	“up-regulates activity”	GLRB	“chemical activation”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 75 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.

Reactome pathways:

Pathway	Partners	Fold	FDR
Neurotransmitter receptors and postsynaptic signal transmission	7	13.2×	2e-04
Transmission across Chemical Synapses	6	8.6×	2e-03

GO biological processes:

GO term	Partners	Fold	FDR
acetylcholine receptor signaling pathway	5	44.6×	2e-05
monoatomic ion transmembrane transport	6	17.8×	2e-04
regulation of membrane potential	5	16.5×	1e-03
monoatomic ion transport	5	11.2×	5e-03
cell surface receptor signaling pathway	7	6.4×	5e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	17
Likely pathogenic	5
Uncertain significance	213
Likely benign	160
Benign	48

Top pathogenic / likely-pathogenic (22)

Variant ID	HGVS	Classification
1064420	NM_000824.5(GLRB):c.1114C>T (p.Gln372Ter)	Pathogenic
1076905	NM_000824.5(GLRB):c.634C>T (p.Arg212Ter)	Pathogenic
1459343	NM_000824.5(GLRB):c.371del (p.Gly124fs)	Pathogenic
16058	NM_000824.5(GLRB):c.752G>A (p.Gly251Asp)	Pathogenic
2095370	NM_000824.5(GLRB):c.618C>G (p.Tyr206Ter)	Pathogenic
2710247	NM_000824.5(GLRB):c.704del (p.Lys235fs)	Pathogenic
2754032	NM_000824.5(GLRB):c.84del (p.Lys31fs)	Pathogenic
2772628	NM_000824.5(GLRB):c.449del (p.Ser150fs)	Pathogenic
3638329	NM_000824.5(GLRB):c.756C>G (p.Tyr252Ter)	Pathogenic
3688899	NM_000824.5(GLRB):c.762del (p.Cys255fs)	Pathogenic
4747421	NM_000824.5(GLRB):c.298-1G>A	Pathogenic
540368	NM_000824.5(GLRB):c.1221dup (p.Val408fs)	Pathogenic
574411	NM_000824.5(GLRB):c.448dup (p.Ser150fs)	Pathogenic
574419	NM_000824.5(GLRB):c.123-2A>G	Pathogenic
582806	NM_000824.5(GLRB):c.472del (p.Gln158fs)	Pathogenic
653331	NM_000824.5(GLRB):c.24del (p.Phe9_Leu10insTer)	Pathogenic
802099	NM_000824.5(GLRB):c.122+1G>A	Pathogenic
1067051	NM_000824.5(GLRB):c.297+1G>T	Likely pathogenic
3236161	NM_000824.5(GLRB):c.790A>T (p.Arg264Trp)	Likely pathogenic
3246671	NC_000004.11:g.(?158091564)(158091880_?)del	Likely pathogenic
4728274	NM_000824.5(GLRB):c.122+1G>C	Likely pathogenic
663950	NC_000004.12:g.(?157170412)(157170748_?)del	Likely pathogenic

SpliceAI

1972 predictions. Top by Δscore:

Variant	Effect	Δscore
4:157076295:CGGG:C	donor_loss	1.0000
4:157076296:GG:G	donor_gain	1.0000
4:157076296:GGGTA:G	donor_loss	1.0000
4:157076297:GG:G	donor_gain	1.0000
4:157076298:G:GA	donor_loss	1.0000
4:157076298:G:GG	donor_gain	1.0000
4:157076299:TAAG:T	donor_loss	1.0000
4:157078114:G:GT	donor_gain	1.0000
4:157078114:G:T	donor_gain	1.0000
4:157078147:G:GG	donor_gain	1.0000
4:157122322:A:AG	acceptor_gain	1.0000
4:157122327:TAGG:T	acceptor_loss	1.0000
4:157122328:A:AG	acceptor_gain	1.0000
4:157122328:A:T	acceptor_loss	1.0000
4:157122329:G:GA	acceptor_gain	1.0000
4:157122329:GGC:G	acceptor_gain	1.0000
4:157122394:AATGG:A	donor_loss	1.0000
4:157122395:ATG:A	donor_gain	1.0000
4:157122395:ATGG:A	donor_loss	1.0000
4:157122396:TGG:T	donor_loss	1.0000
4:157122397:GGT:G	donor_loss	1.0000
4:157122398:G:GC	donor_loss	1.0000
4:157122398:G:GG	donor_gain	1.0000
4:157122399:T:TC	donor_loss	1.0000
4:157136882:GAGCT:G	donor_gain	1.0000
4:157136884:GCT:G	donor_gain	1.0000
4:157136887:G:GG	donor_gain	1.0000
4:157138805:A:AG	acceptor_gain	1.0000
4:157138805:ATAG:A	acceptor_loss	1.0000
4:157138806:T:G	acceptor_gain	1.0000

AlphaMissense

3273 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
4:157120651:C:A	P73Q	1.000
4:157122397:G:A	M99I	1.000
4:157122397:G:C	M99I	1.000
4:157122397:G:T	M99I	1.000
4:157136491:T:C	L107P	1.000
4:157136502:T:A	W111R	1.000
4:157136502:T:C	W111R	1.000
4:157136504:G:C	W111C	1.000
4:157136504:G:T	W111C	1.000
4:157136518:T:C	L116P	1.000
4:157136586:T:A	W139R	1.000
4:157136586:T:C	W139R	1.000
4:157136588:G:C	W139C	1.000
4:157136588:G:T	W139C	1.000
4:157136601:T:C	F144L	1.000
4:157136603:T:A	F144L	1.000
4:157136603:T:G	F144L	1.000
4:157136651:C:A	N160K	1.000
4:157136651:C:G	N160K	1.000
4:157136656:T:C	L162P	1.000
4:157136683:T:A	V171D	1.000
4:157136691:A:C	S174R	1.000
4:157136693:C:A	S174R	1.000
4:157136693:C:G	S174R	1.000
4:157136698:G:C	R176T	1.000
4:157136698:G:T	R176M	1.000
4:157136823:T:C	C183R	1.000
4:157136824:G:A	C183Y	1.000
4:157136825:C:G	C183W	1.000
4:157136853:G:C	D193H	1.000

dbSNP variants (sampled 300 via entrez): RS1000018067 (4:157171004 C>A,T), RS1000087983 (4:157145891 G>A,C), RS1000102846 (4:157158101 T>A), RS1000125058 (4:157094805 G>A), RS1000176149 (4:157077360 C>T), RS1000184566 (4:157121152 A>C), RS1000217870 (4:157117602 G>A,T), RS1000218558 (4:157098135 A>G), RS1000248849 (4:157164316 G>C), RS1000255246 (4:157141210 C>T), RS1000317123 (4:157110442 A>G,T), RS1000343718 (4:157083440 G>A), RS1000357852 (4:157089262 G>A,T), RS1000396251 (4:157083660 T>A,C), RS1000396815 (4:157135063 T>C)

Disease associations

OMIM: gene MIM:138492 | disease phenotypes: MIM:614619

GenCC curated gene-disease

Disease	Classification	Inheritance
hyperekplexia 2	Definitive	Autosomal recessive
hereditary hyperekplexia	Supportive	Autosomal dominant

Mondo (2): hyperekplexia 2 (MONDO:0013828), hereditary hyperekplexia (MONDO:0021022)

Orphanet (1): Hereditary hyperekplexia (Orphanet:3197)

HPO phenotypes

31 total (30 of 31 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000483	Astigmatism
HP:0000545	Myopia
HP:0000565	Esotropia
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001251	Ataxia
HP:0001257	Spasticity
HP:0001270	Motor delay
HP:0001276	Hypertonia
HP:0001288	Gait disturbance
HP:0001336	Myoclonus
HP:0001347	Hyperreflexia
HP:0001373	Joint dislocation
HP:0001387	Joint stiffness
HP:0001537	Umbilical hernia
HP:0002020	Gastroesophageal reflux
HP:0002036	Hiatus hernia
HP:0002063	Rigidity
HP:0002267	Exaggerated startle response
HP:0002360	Sleep disturbance
HP:0002380	Fasciculations
HP:0002827	Hip dislocation
HP:0003552	Muscle stiffness
HP:0003577	Congenital onset
HP:0003623	Neonatal onset
HP:0010519	Increased fetal movement
HP:0030904	Glabellar reflex
HP:0100022	Abnormality of movement
HP:0100633	Esophagitis

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST003901_20	Cognitive decline (age-related)	6.000000e-06
GCST009615_7	Triglyceride levels x loop diuretics use interaction	2.000000e-06

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004530	triglyceride measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (3): CHEMBL2363052 (PROTEIN COMPLEX), CHEMBL4106144 (PROTEIN COMPLEX), CHEMBL4296075 (PROTEIN COMPLEX)

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

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs17035723	GLRB		0.00	0

GtoPdb / IUPHAR curated pharmacology

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

Target class: lgic — Glycine receptors

Most potent curated ligand interactions (11 total), top 11:

Ligand	Action	Affinity	Parameter
ginkgolide B	Channel blocker	6.3	pIC50
tropisetron	Antagonist	5.3	pKi
cyanotriphenylborate	Channel blocker	5.1	pIC50
pregnenolone sulphate	Antagonist	5.0	pKi
nifedipine	Antagonist	4.9	pIC50
picrotoxinin	Channel blocker	4.6	pIC50
picrotin	Channel blocker	4.6	pIC50
bilobalide	Antagonist	3.7	pIC50
picrotoxin	Channel blocker	3.7	pIC50
Zn2+	Inhibition	3.7	pIC50
ginkgolide X	Antagonist	3.5	pIC50

Binding affinities (BindingDB)

1 measured of 1 human assays (1 total across all organisms); most potent 1 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value
Gelsemine	IC50	30000 nM

ChEMBL bioactivities

130 potent at pChembl≥5 of 144 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.87	EC50	13.49	nM	CHEMBL4227298
7.80	EC50	16	nM	CHEMBL4070615
7.37	IC50	43	nM	CHEMBL4103909
7.34	IC50	46	nM	CHEMBL4079657
7.25	IC50	56	nM	CHEMBL4102677
7.24	IC50	58	nM	STRYCHNINE
7.22	IC50	60	nM	STRYCHNINE
7.18	EC50	66	nM	CHEMBL4070615
7.10	IC50	80	nM	CHEMBL4089150
7.01	IC50	97	nM	CHEMBL4060962
6.94	IC50	116	nM	CHEMBL4068867
6.83	IC50	147	nM	CHEMBL4518537
6.82	IC50	150	nM	CHEMBL4079657
6.80	IC50	158.5	nM	CHEMBL4079657
6.77	EC50	171	nM	CHEMBL4074873
6.75	IC50	180	nM	STRYCHNINE
6.74	IC50	182	nM	STRYCHNINE
6.69	IC50	204.2	nM	CHEMBL4865584
6.68	IC50	210	nM	CHEMBL4102677
6.68	IC50	210	nM	CHEMBL4089150
6.68	IC50	210	nM	CHEMBL4865584
6.67	IC50	213.8	nM	CHEMBL4089150
6.67	IC50	213.8	nM	CHEMBL4102677
6.62	IC50	240	nM	CHEMBL4103909
6.62	IC50	239.9	nM	CHEMBL4103909
6.57	IC50	270	nM	CHEMBL4060962
6.56	IC50	275.4	nM	CHEMBL4060962
6.52	EC50	300	nM	CHEMBL4083687
6.51	IC50	310	nM	CHEMBL4086212
6.51	IC50	309	nM	CHEMBL4086212
6.51	IC50	311	nM	CHEMBL4096857
6.48	EC50	330	nM	CHEMBL4074873
6.46	IC50	350	nM	CHEMBL4068867
6.45	IC50	354.8	nM	CHEMBL4068867
6.43	EC50	370	nM	CHEMBL4083687
6.30	EC50	500	nM	CHEMBL4282578
6.29	IC50	512.9	nM	STRYCHNINE
6.29	IC50	510	nM	STRYCHNINE
6.29	IC50	510	nM	CHEMBL4849489
6.29	IC50	512.9	nM	CHEMBL4849489
6.22	EC50	600	nM	CHEMBL4284872
6.18	IC50	660.7	nM	CHEMBL4096505
6.18	EC50	660.7	nM	CHEMBL4227048
6.17	IC50	670	nM	CHEMBL4096505
6.17	IC50	680	nM	CHEMBL4870655
6.17	IC50	676.1	nM	CHEMBL4870655
6.16	EC50	700	nM	CHEMBL4284872
6.15	IC50	710	nM	CHEMBL4087535
6.15	IC50	708	nM	CHEMBL4087535
6.11	IC50	780	nM	CHEMBL4066164

PubChem BioAssay actives

130 with measured affinity, of 402 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
3,5-ditert-butyl-2,6-dihydroxybenzoic acid	1388379: Positive allosteric modulation of human GlyRalpha3beta expressed in CHO cells assessed as potentiation of EC20 glycine-induced ion flux by HT assay	ec50	0.0135	uM
(3S,3aS,9bS)-2-(1,3-benzodioxol-5-ylsulfonyl)-3,5-dimethyl-1,3,3a,9b-tetrahydropyrrolo[3,4-c][1,6]naphthyridin-4-one	1388057: Positive allosteric modulation of human glycine alpha1beta receptor expressed in HEK293T cells assessed as glycine-induced increase in current response after 18 to 24 hrs by membrane potential blue dye based FLIPR assay	ec50	0.0160	uM
(4aR,5aS,8aR,13aS,15E,15aR,15bR)-15-prop-2-ynoxyimino-2,4a,5,5a,7,8,13a,15a,15b,16-decahydro4,6-methanoindolo[3,2,1-ij]oxepino[2,3,4-de]pyrrolo[2,3-h]quinolin-14-one	1431420: Antagonist activity at recombinant human glycine receptor alpha 1 beta expressed in HEK293 cells assessed as inhibition of glycine-induced current at -50mV holding potential by whole cell patch-clamp method	ic50	0.0430	uM
(4aR,5aS,8aR,13aS,15E,15aR,15bR)-15-prop-2-enoxyimino-2,4a,5,5a,7,8,13a,15a,15b,16-decahydro4,6-methanoindolo[3,2,1-ij]oxepino[2,3,4-de]pyrrolo[2,3-h]quinolin-14-one	1431420: Antagonist activity at recombinant human glycine receptor alpha 1 beta expressed in HEK293 cells assessed as inhibition of glycine-induced current at -50mV holding potential by whole cell patch-clamp method	ic50	0.0460	uM
(4aR,5aS,8aR,13aS,15E,15aR,15bR)-15-methoxyimino-2,4a,5,5a,7,8,13a,15a,15b,16-decahydro4,6-methanoindolo[3,2,1-ij]oxepino[2,3,4-de]pyrrolo[2,3-h]quinolin-14-one	1431420: Antagonist activity at recombinant human glycine receptor alpha 1 beta expressed in HEK293 cells assessed as inhibition of glycine-induced current at -50mV holding potential by whole cell patch-clamp method	ic50	0.0560	uM
(4aR,5aS,8aR,13aS,15aS,15bR)-4a,5,5a,7,8,13a,15,15a,15b,16-decahydro-2H-4,6-methanoindolo[3,2,1-ij]oxepino[2,3,4-de]pyrrolo[2,3-h]quinolin-14-one	1431420: Antagonist activity at recombinant human glycine receptor alpha 1 beta expressed in HEK293 cells assessed as inhibition of glycine-induced current at -50mV holding potential by whole cell patch-clamp method	ic50	0.0580	uM
(4aR,5aS,8aR,13aS,15E,15aR,15bR)-15-hydroxyimino-2,4a,5,5a,7,8,13a,15a,15b,16-decahydro4,6-methanoindolo[3,2,1-ij]oxepino[2,3,4-de]pyrrolo[2,3-h]quinolin-14-one	1431420: Antagonist activity at recombinant human glycine receptor alpha 1 beta expressed in HEK293 cells assessed as inhibition of glycine-induced current at -50mV holding potential by whole cell patch-clamp method	ic50	0.0800	uM
(4aR,5aS,8aR,13aS,15aS,15bR)-10-amino-4a,5,5a,7,8,13a,15,15a,15b,16-decahydro-2H-4,6-methanoindolo[3,2,1-ij]oxepino[2,3,4-de]pyrrolo[2,3-h]quinolin-14-one	1431420: Antagonist activity at recombinant human glycine receptor alpha 1 beta expressed in HEK293 cells assessed as inhibition of glycine-induced current at -50mV holding potential by whole cell patch-clamp method	ic50	0.0970	uM
(4aR,5aS,8aR,13aS,15E,15aR,15bR)-15-propoxyimino-2,4a,5,5a,7,8,13a,15a,15b,16-decahydro4,6-methanoindolo[3,2,1-ij]oxepino[2,3,4-de]pyrrolo[2,3-h]quinolin-14-one	1431420: Antagonist activity at recombinant human glycine receptor alpha 1 beta expressed in HEK293 cells assessed as inhibition of glycine-induced current at -50mV holding potential by whole cell patch-clamp method	ic50	0.1160	uM
N-[(4aR,5aS,8aR,13aS,15S,15aR,15bR)-14-oxo-4a,5,5a,7,8,13a,15,15a,15b,16-decahydro-2H-4,6-methanoindolo[3,2,1-ij]oxepino[2,3,4-de]pyrrolo[2,3-h]quinolin-15-yl]propanamide	1545116: Antagonist activity at human glycine receptor subunit alpha-1beta expressed in HEK293 cells assessed as reduction in glycine-induced whole cell currents by patch-clamp technique	ic50	0.1470	uM
(3aS,9bS)-2-(1-benzofuran-5-ylsulfonyl)-5-methyl-1,3,3a,9b-tetrahydropyrrolo[3,4-c][1,6]naphthyridin-4-one	1388057: Positive allosteric modulation of human glycine alpha1beta receptor expressed in HEK293T cells assessed as glycine-induced increase in current response after 18 to 24 hrs by membrane potential blue dye based FLIPR assay	ec50	0.1710	uM
N,N’-bis[(4aR,5aS,8aR,13aS,15aS,15bR)-14-oxo-4a,5,5a,7,8,13a,15,15a,15b,16-decahydro-2H-4,6-methanoindolo[3,2,1-ij]oxepino[2,3,4-de]pyrrolo[2,3-h]quinolin-10-yl]tetradecanediamide	1761884: Antagonist activity at human glycine receptor subunit alpha-1beta expressed in human tsA201 cells assessed as reduction in glycine-induced response incubated for 30 mins by fluorescence-based FLIPR membrane potential blue assay	ic50	0.2042	uM
(3aS,9bS)-2-(1,3-benzodioxol-5-ylsulfonyl)-5-methyl-1,3,3a,9b-tetrahydropyrrolo[3,4-c]quinolin-4-one	1401008: Positive allosteric modulation of human GlyRalpha1beta assessed as increase in glycine-induced chloride ion flux by FLIPR assay	ec50	0.3000	uM
(4aR,5aS,8aR,13aS,15E,15aR,15bR)-15-phenylmethoxyimino-2,4a,5,5a,7,8,13a,15a,15b,16-decahydro4,6-methanoindolo[3,2,1-ij]oxepino[2,3,4-de]pyrrolo[2,3-h]quinolin-14-one	1431418: Antagonist activity at recombinant human glycine receptor alpha 1 beta expressed in human tsA201 cells assessed as inhibition of glycine-induced receptor activation after 30 mins by FLIPR membrane potential blue assay	ic50	0.3090	uM
N-[(4aR,5aS,8aR,13aS,15aS,15bR)-14-oxo-4a,5,5a,7,8,13a,15,15a,15b,16-decahydro-2H-4,6-methanoindolo[3,2,1-ij]oxepino[2,3,4-de]pyrrolo[2,3-h]quinolin-10-yl]propanamide	1431420: Antagonist activity at recombinant human glycine receptor alpha 1 beta expressed in HEK293 cells assessed as inhibition of glycine-induced current at -50mV holding potential by whole cell patch-clamp method	ic50	0.3110	uM
1-(1,3-benzodioxol-5-ylsulfonyl)-3-(5-chloro-2-methoxyphenoxy)azetidine	1400990: Positive allosteric modulation of human GlyRalpha3beta expressed in HEK293T cells assessed as increase in glycine-induced chloride ion flux measured for 4 mins by FLIPR assay	ec50	0.5000	uM
N-[2-[[(4aR,5aS,8aR,13aS,15aS,15bR)-14-oxo-4a,5,5a,7,8,13a,15,15a,15b,16-decahydro-2H-4,6-methanoindolo[3,2,1-ij]oxepino[2,3,4-de]pyrrolo[2,3-h]quinolin-10-yl]amino]-2-oxoethyl]octanamide	1761884: Antagonist activity at human glycine receptor subunit alpha-1beta expressed in human tsA201 cells assessed as reduction in glycine-induced response incubated for 30 mins by fluorescence-based FLIPR membrane potential blue assay	ic50	0.5100	uM
6-[3-(5-chloro-2-methoxyphenoxy)azetidin-1-yl]sulfonyl-3H-1,3-benzoxazol-2-one	1401008: Positive allosteric modulation of human GlyRalpha1beta assessed as increase in glycine-induced chloride ion flux by FLIPR assay	ec50	0.6000	uM
methyl 2-[(E)-[(4aR,5aS,8aR,13aS,15aR,15bR)-14-oxo-2,4a,5,5a,7,8,13a,15a,15b,16-decahydro4,6-methanoindolo[3,2,1-ij]oxepino[2,3,4-de]pyrrolo[2,3-h]quinolin-15-ylidene]amino]oxyacetate	1431418: Antagonist activity at recombinant human glycine receptor alpha 1 beta expressed in human tsA201 cells assessed as inhibition of glycine-induced receptor activation after 30 mins by FLIPR membrane potential blue assay	ic50	0.6607	uM
4-[[(2R)-8-fluoro-3-oxo-4-[[2-(trifluoromethyl)phenyl]methyl]-1,4-benzothiazin-2-yl]methyl]benzoic acid	1388379: Positive allosteric modulation of human GlyRalpha3beta expressed in CHO cells assessed as potentiation of EC20 glycine-induced ion flux by HT assay	ec50	0.6607	uM
N-[(4aR,5aS,8aR,13aS,15aS,15bR)-14-oxo-4a,5,5a,7,8,13a,15,15a,15b,16-decahydro-2H-4,6-methanoindolo[3,2,1-ij]oxepino[2,3,4-de]pyrrolo[2,3-h]quinolin-10-yl]octanamide	1761884: Antagonist activity at human glycine receptor subunit alpha-1beta expressed in human tsA201 cells assessed as reduction in glycine-induced response incubated for 30 mins by fluorescence-based FLIPR membrane potential blue assay	ic50	0.6761	uM
(4aR,5aS,8aR,13aS,15E,15aR,15bR)-15-pentoxyimino-2,4a,5,5a,7,8,13a,15a,15b,16-decahydro4,6-methanoindolo[3,2,1-ij]oxepino[2,3,4-de]pyrrolo[2,3-h]quinolin-14-one	1431418: Antagonist activity at recombinant human glycine receptor alpha 1 beta expressed in human tsA201 cells assessed as inhibition of glycine-induced receptor activation after 30 mins by FLIPR membrane potential blue assay	ic50	0.7079	uM
(4aR,5aS,8aR,13aS,15E,15aR,15bR)-15-(2-phenylethoxyimino)-2,4a,5,5a,7,8,13a,15a,15b,16-decahydro4,6-methanoindolo[3,2,1-ij]oxepino[2,3,4-de]pyrrolo[2,3-h]quinolin-14-one	1431418: Antagonist activity at recombinant human glycine receptor alpha 1 beta expressed in human tsA201 cells assessed as inhibition of glycine-induced receptor activation after 30 mins by FLIPR membrane potential blue assay	ic50	0.7762	uM
N,N’-bis[(4aR,5aS,8aR,13aS,15aS,15bR)-14-oxo-4a,5,5a,7,8,13a,15,15a,15b,16-decahydro-2H-4,6-methanoindolo[3,2,1-ij]oxepino[2,3,4-de]pyrrolo[2,3-h]quinolin-10-yl]dodecanediamide	1761886: Antagonist activity at human glycine receptor subunit alpha-1beta expressed in HEK293 cells assessed as reduction in glycine-induced currents by whole-cell patch-clamp assay	ic50	0.8000	uM
(4aR,5aS,8aR,13aS,15E,15aR,15bR)-15-butoxyimino-2,4a,5,5a,7,8,13a,15a,15b,16-decahydro4,6-methanoindolo[3,2,1-ij]oxepino[2,3,4-de]pyrrolo[2,3-h]quinolin-14-one	1431418: Antagonist activity at recombinant human glycine receptor alpha 1 beta expressed in human tsA201 cells assessed as inhibition of glycine-induced receptor activation after 30 mins by FLIPR membrane potential blue assay	ic50	0.8710	uM
N,N’-bis[2-[[(4aR,5aS,8aR,13aS,15aS,15bR)-14-oxo-4a,5,5a,7,8,13a,15,15a,15b,16-decahydro-2H-4,6-methanoindolo[3,2,1-ij]oxepino[2,3,4-de]pyrrolo[2,3-h]quinolin-10-yl]amino]-2-oxoethyl]decanediamide	1761884: Antagonist activity at human glycine receptor subunit alpha-1beta expressed in human tsA201 cells assessed as reduction in glycine-induced response incubated for 30 mins by fluorescence-based FLIPR membrane potential blue assay	ic50	0.8710	uM
5-[3-(5-chloro-2-methoxyphenoxy)azetidin-1-yl]sulfonyl-1,3-benzothiazole	1400990: Positive allosteric modulation of human GlyRalpha3beta expressed in HEK293T cells assessed as increase in glycine-induced chloride ion flux measured for 4 mins by FLIPR assay	ec50	0.9000	uM
5-[3-(5-chloro-2-methoxyphenoxy)azetidin-1-yl]sulfonyl-1H-indazole	1400990: Positive allosteric modulation of human GlyRalpha3beta expressed in HEK293T cells assessed as increase in glycine-induced chloride ion flux measured for 4 mins by FLIPR assay	ec50	0.9000	uM
(4aR,5aS,8aR,13aS,15E,15aR,15bR)-15-(2-methylpropoxyimino)-2,4a,5,5a,7,8,13a,15a,15b,16-decahydro4,6-methanoindolo[3,2,1-ij]oxepino[2,3,4-de]pyrrolo[2,3-h]quinolin-14-one	1431418: Antagonist activity at recombinant human glycine receptor alpha 1 beta expressed in human tsA201 cells assessed as inhibition of glycine-induced receptor activation after 30 mins by FLIPR membrane potential blue assay	ic50	1.1000	uM
1-(1,3-benzodioxol-5-ylsulfonyl)-3-(5-fluoro-2-methoxyphenoxy)azetidine	1400990: Positive allosteric modulation of human GlyRalpha3beta expressed in HEK293T cells assessed as increase in glycine-induced chloride ion flux measured for 4 mins by FLIPR assay	ec50	1.2100	uM
N,N’-bis[(4aR,5aS,8aR,13aS,15aS,15bR)-14-oxo-4a,5,5a,7,8,13a,15,15a,15b,16-decahydro-2H-4,6-methanoindolo[3,2,1-ij]oxepino[2,3,4-de]pyrrolo[2,3-h]quinolin-10-yl]octanediamide	1761886: Antagonist activity at human glycine receptor subunit alpha-1beta expressed in HEK293 cells assessed as reduction in glycine-induced currents by whole-cell patch-clamp assay	ic50	1.3000	uM
methyl 5-[(E)-[(4aR,5aS,8aR,13aS,15aR,15bR)-14-oxo-2,4a,5,5a,7,8,13a,15a,15b,16-decahydro4,6-methanoindolo[3,2,1-ij]oxepino[2,3,4-de]pyrrolo[2,3-h]quinolin-15-ylidene]amino]oxypentanoate	1431418: Antagonist activity at recombinant human glycine receptor alpha 1 beta expressed in human tsA201 cells assessed as inhibition of glycine-induced receptor activation after 30 mins by FLIPR membrane potential blue assay	ic50	1.4791	uM
N,N’-bis[2-[[(4aR,5aS,8aR,13aS,15aS,15bR)-14-oxo-4a,5,5a,7,8,13a,15,15a,15b,16-decahydro-2H-4,6-methanoindolo[3,2,1-ij]oxepino[2,3,4-de]pyrrolo[2,3-h]quinolin-10-yl]amino]-2-oxoethyl]nonanediamide	1761884: Antagonist activity at human glycine receptor subunit alpha-1beta expressed in human tsA201 cells assessed as reduction in glycine-induced response incubated for 30 mins by fluorescence-based FLIPR membrane potential blue assay	ic50	1.7000	uM
N-[(4aR,5aS,8aR,13aS,15aS,15bR)-14-oxo-4a,5,5a,7,8,13a,15,15a,15b,16-decahydro-2H-4,6-methanoindolo[3,2,1-ij]oxepino[2,3,4-de]pyrrolo[2,3-h]quinolin-10-yl]-5-[3-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[3-[[5-[[(4aR,5aS,8aR,13aS,15aS,15bR)-14-oxo-4a,5,5a,7,8,13a,15,15a,15b,16-decahydro-2H-4,6-methanoindolo[3,2,1-ij]oxepino[2,3,4-de]pyrrolo[2,3-h]quinolin-10-yl]amino]-5-oxopentyl]amino]-3-oxopropoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]propanoylamino]pentanamide	1761884: Antagonist activity at human glycine receptor subunit alpha-1beta expressed in human tsA201 cells assessed as reduction in glycine-induced response incubated for 30 mins by fluorescence-based FLIPR membrane potential blue assay	ic50	1.7783	uM
N,N’-bis[(4aR,5aS,8aR,13aS,15aS,15bR)-14-oxo-4a,5,5a,7,8,13a,15,15a,15b,16-decahydro-2H-4,6-methanoindolo[3,2,1-ij]oxepino[2,3,4-de]pyrrolo[2,3-h]quinolin-10-yl]decanediamide	1761886: Antagonist activity at human glycine receptor subunit alpha-1beta expressed in HEK293 cells assessed as reduction in glycine-induced currents by whole-cell patch-clamp assay	ic50	1.9000	uM
N,N’-bis[2-[[(4aR,5aS,8aR,13aS,15aS,15bR)-14-oxo-4a,5,5a,7,8,13a,15,15a,15b,16-decahydro-2H-4,6-methanoindolo[3,2,1-ij]oxepino[2,3,4-de]pyrrolo[2,3-h]quinolin-10-yl]amino]-2-oxoethyl]dodecanediamide	1761884: Antagonist activity at human glycine receptor subunit alpha-1beta expressed in human tsA201 cells assessed as reduction in glycine-induced response incubated for 30 mins by fluorescence-based FLIPR membrane potential blue assay	ic50	1.9000	uM
N,N’-bis[2-[[(4aR,5aS,8aR,13aS,15aS,15bR)-14-oxo-4a,5,5a,7,8,13a,15,15a,15b,16-decahydro-2H-4,6-methanoindolo[3,2,1-ij]oxepino[2,3,4-de]pyrrolo[2,3-h]quinolin-10-yl]amino]-2-oxoethyl]tetradecanediamide	1761884: Antagonist activity at human glycine receptor subunit alpha-1beta expressed in human tsA201 cells assessed as reduction in glycine-induced response incubated for 30 mins by fluorescence-based FLIPR membrane potential blue assay	ic50	1.9953	uM
(2S,3S)-1-(1,3-benzodioxol-5-ylsulfonyl)-3-(5-chloro-2-methoxyphenoxy)-2-methylazetidine	1400990: Positive allosteric modulation of human GlyRalpha3beta expressed in HEK293T cells assessed as increase in glycine-induced chloride ion flux measured for 4 mins by FLIPR assay	ec50	2.1000	uM
1,1,1-trifluoro-2-[4-[[2-piperidin-1-yl-4-(trifluoromethyl)-4,5-dihydro-1,3-thiazol-5-yl]sulfonyl]phenyl]propan-2-ol	1400990: Positive allosteric modulation of human GlyRalpha3beta expressed in HEK293T cells assessed as increase in glycine-induced chloride ion flux measured for 4 mins by FLIPR assay	ec50	2.2000	uM
2-[4-[[2-ethylimino-4-(trifluoromethyl)-1,3-thiazolidin-5-yl]sulfonyl]phenyl]-1,1,1-trifluoropropan-2-ol	1400990: Positive allosteric modulation of human GlyRalpha3beta expressed in HEK293T cells assessed as increase in glycine-induced chloride ion flux measured for 4 mins by FLIPR assay	ec50	2.2000	uM
N,N’-bis[2-[[(4aR,5aS,8aR,13aS,15aS,15bR)-14-oxo-4a,5,5a,7,8,13a,15,15a,15b,16-decahydro-2H-4,6-methanoindolo[3,2,1-ij]oxepino[2,3,4-de]pyrrolo[2,3-h]quinolin-10-yl]amino]-2-oxoethyl]heptanediamide	1761884: Antagonist activity at human glycine receptor subunit alpha-1beta expressed in human tsA201 cells assessed as reduction in glycine-induced response incubated for 30 mins by fluorescence-based FLIPR membrane potential blue assay	ic50	2.2000	uM
N,N’-bis[2-[[(4aR,5aS,8aR,13aS,15aS,15bR)-14-oxo-4a,5,5a,7,8,13a,15,15a,15b,16-decahydro-2H-4,6-methanoindolo[3,2,1-ij]oxepino[2,3,4-de]pyrrolo[2,3-h]quinolin-10-yl]amino]-2-oxoethyl]hexadecanediamide	1761884: Antagonist activity at human glycine receptor subunit alpha-1beta expressed in human tsA201 cells assessed as reduction in glycine-induced response incubated for 30 mins by fluorescence-based FLIPR membrane potential blue assay	ic50	2.2000	uM
6-[3-(5-chloro-2-methoxyphenoxy)azetidin-1-yl]sulfonyl-1H-indazole	1400990: Positive allosteric modulation of human GlyRalpha3beta expressed in HEK293T cells assessed as increase in glycine-induced chloride ion flux measured for 4 mins by FLIPR assay	ec50	2.3000	uM
1-(1,3-benzodioxol-5-ylsulfonyl)-3-(2-methoxyphenoxy)azetidine	1400990: Positive allosteric modulation of human GlyRalpha3beta expressed in HEK293T cells assessed as increase in glycine-induced chloride ion flux measured for 4 mins by FLIPR assay	ec50	2.3000	uM
N,N’-bis[2-[[(4aR,5aS,8aR,13aS,15aS,15bR)-14-oxo-4a,5,5a,7,8,13a,15,15a,15b,16-decahydro-2H-4,6-methanoindolo[3,2,1-ij]oxepino[2,3,4-de]pyrrolo[2,3-h]quinolin-10-yl]amino]-2-oxoethyl]octanediamide	1761884: Antagonist activity at human glycine receptor subunit alpha-1beta expressed in human tsA201 cells assessed as reduction in glycine-induced response incubated for 30 mins by fluorescence-based FLIPR membrane potential blue assay	ic50	2.3988	uM
5-[3-(5-chloro-2-methoxyphenoxy)azetidin-1-yl]sulfonyl-1-methylbenzimidazole	1400990: Positive allosteric modulation of human GlyRalpha3beta expressed in HEK293T cells assessed as increase in glycine-induced chloride ion flux measured for 4 mins by FLIPR assay	ec50	2.5000	uM
(2R,3R)-1-(1,3-benzodioxol-5-ylsulfonyl)-3-(5-chloro-2-methoxyphenoxy)-2-methylazetidine	1400990: Positive allosteric modulation of human GlyRalpha3beta expressed in HEK293T cells assessed as increase in glycine-induced chloride ion flux measured for 4 mins by FLIPR assay	ec50	2.7000	uM
1-(1,3-benzodioxol-5-ylsulfonyl)-3-(2-methoxy-5-methylphenoxy)azetidine	1400990: Positive allosteric modulation of human GlyRalpha3beta expressed in HEK293T cells assessed as increase in glycine-induced chloride ion flux measured for 4 mins by FLIPR assay	ec50	3.1000	uM
5-[3-(5-chloro-2-methoxyphenoxy)azetidin-1-yl]sulfonyl-1-methylindazole	1400990: Positive allosteric modulation of human GlyRalpha3beta expressed in HEK293T cells assessed as increase in glycine-induced chloride ion flux measured for 4 mins by FLIPR assay	ec50	3.3000	uM
N-[(4aR,5aS,8aR,13aS,15aS,15bR)-14-oxo-4a,5,5a,7,8,13a,15,15a,15b,16-decahydro-2H-4,6-methanoindolo[3,2,1-ij]oxepino[2,3,4-de]pyrrolo[2,3-h]quinolin-10-yl]-11-[3-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[3-[[11-[[(4aR,5aS,8aR,13aS,15aS,15bR)-14-oxo-4a,5,5a,7,8,13a,15,15a,15b,16-decahydro-2H-4,6-methanoindolo[3,2,1-ij]oxepino[2,3,4-de]pyrrolo[2,3-h]quinolin-10-yl]amino]-11-oxoundecyl]amino]-3-oxopropoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]propanoylamino]undecanamide	1761884: Antagonist activity at human glycine receptor subunit alpha-1beta expressed in human tsA201 cells assessed as reduction in glycine-induced response incubated for 30 mins by fluorescence-based FLIPR membrane potential blue assay	ic50	3.8904	uM

CTD chemical–gene interactions

37 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	increases expression	5
entinostat	affects cotreatment, decreases expression	2
Nickel	decreases expression	2
Cadmium Chloride	increases abundance, increases expression, decreases expression	2
aristolochic acid I	decreases expression	1
methylmercuric chloride	decreases expression	1
bisphenol A	increases expression	1
trichostatin A	increases expression	1
mono-(2-ethylhexyl)phthalate	decreases methylation, increases abundance	1
potassium chromate(VI)	decreases expression	1
nickel sulfate	decreases expression	1
perfluorooctane sulfonic acid	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
abrine	decreases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
bisphenol S	increases expression	1
jinfukang	decreases expression	1
(+)-JQ1 compound	increases expression	1
Temozolomide	affects response to substance	1
Vorinostat	increases expression	1
Air Pollutants	decreases expression, increases abundance	1
Benzo(a)pyrene	decreases methylation, affects methylation	1
Cadmium	increases abundance, increases expression	1
Carmustine	affects response to substance	1
Cyclophosphamide	increases expression	1
Diethylhexyl Phthalate	decreases methylation, increases abundance	1
Doxorubicin	decreases expression	1
Estradiol	decreases expression, affects cotreatment	1
Lead	affects expression	1
Ouabain	increases expression	1

ChEMBL screening assays

30 unique, capped per target: 29 binding, 1 toxicity

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL3998488	Binding	Antagonist activity at recombinant human glycine receptor alpha 1 beta expressed in human tsA201 cells assessed as inhibition of glycine-induced receptor activation after 30 mins by FLIPR membrane potential blue assay	Oxime Ethers of (E)-11-Isonitrosostrychnine as Highly Potent Glycine Receptor Antagonists. — J Nat Prod
CHEMBL6108592	Toxicity	Inhibition of glycine receptor alpha1beta (unknown origin)	Discovery of BT-114143, a Novel and Potent Phosphoric Acid-Containing Small-Molecule Plasminogen Activation Inhibitor for Hyperfibrinolysis. — J Med Chem

Cellosaurus cell lines

2 cell lines: 2 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_SQ06	HAP1 GLRB (-) 1	Cancer cell line	Male
CVCL_SQ07	HAP1 GLRB (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT01476514	Not specified	TERMINATED	Effects of Mutations of the Glycine Gene Associated With Hyperekplexia on Central Pain Processing
NCT05168969	Not specified	COMPLETED	Hyperekplexia in Patients With CTNNB1 Mutation
NCT05652101	Not specified	RECRUITING	Hyperekplexia : Adaptative Skills and Neurodevelopmental Trajectory
NCT05687474	Not specified	COMPLETED	Baby Detect : Genomic Newborn Screening