GLRA1

Summary

GLRA1 (glycine receptor alpha 1, HGNC:4326) is a protein-coding gene on chromosome 5q33.1, encoding Glycine receptor subunit alpha-1 (P23415). Subunit of heteromeric glycine-gated chloride channels.

The protein encoded by this gene is a subunit of a pentameric inhibitory glycine receptor, which mediates postsynaptic inhibition in the central nervous system. Defects in this gene are a cause of startle disease (STHE), also known as hereditary hyperekplexia or congenital stiff-person syndrome. Multiple transcript variants encoding different isoforms have been found.

Source: NCBI Gene 2741 — RefSeq curated summary.

At a glance

• Gene–disease (curated): hyperekplexia 1 (Definitive, GenCC) — +1 more curated relationship
• GWAS associations: 1
• Clinical variants (ClinVar): 587 total — 50 pathogenic, 27 likely-pathogenic
• Phenotypes (HPO): 31
• Druggable target: yes — 15 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_000171

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:4326
Approved symbol	GLRA1
Name	glycine receptor alpha 1
Location	5q33.1
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000145888
Ensembl biotype	protein_coding
OMIM	138491
Entrez	2741

Gene structure

Transcript identifiers

Ensembl transcripts: 4 — 2 protein_coding, 1 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000274576, ENST00000455880, ENST00000462581, ENST00000471351

RefSeq mRNA: 3 — MANE Select: NM_000171 NM_000171, NM_001146040, NM_001292000

CCDS: CCDS4320, CCDS54942

Canonical transcript exons

ENST00000274576 — 9 exons

Exon	Start	End
ENSE00001342918	151924494	151924851
ENSE00002132366	151822513	151822963
ENSE00003460981	151892311	151892438
ENSE00003461042	151856301	151856383
ENSE00003528981	151855040	151855177
ENSE00003534995	151859785	151860008
ENSE00003572692	151886721	151886788
ENSE00003594394	151851390	151851604
ENSE00003595147	151828921	151829067

Expression profiles

Bgee: expression breadth broad, 39 present calls, max score 78.74.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.2431 / max 53.6634, expressed in 54 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
64440	0.2227	51
64441	0.0204	13

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
islet of Langerhans	UBERON:0000006	78.74	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	78.47	gold quality
pancreatic ductal cell	CL:0002079	60.65	silver quality
decidua	UBERON:0002450	56.55	gold quality
hypothalamus	UBERON:0001898	56.22	gold quality
tibialis anterior	UBERON:0001385	55.10	silver quality
ileal mucosa	UBERON:0000331	55.06	silver quality
pancreas	UBERON:0001264	54.81	gold quality
substantia nigra	UBERON:0002038	52.49	gold quality
hair follicle	UBERON:0002073	52.43	gold quality
epithelial cell of pancreas	CL:0000083	51.31	gold quality
midbrain	UBERON:0001891	51.17	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	50.78	gold quality
spinal cord	UBERON:0002240	49.85	gold quality
deltoid	UBERON:0001476	49.61	gold quality
buccal mucosa cell	CL:0002336	49.60	gold quality
Brodmann (1909) area 46	UBERON:0006483	49.30	gold quality
cervix squamous epithelium	UBERON:0006922	49.20	gold quality
quadriceps femoris	UBERON:0001377	49.10	gold quality
olfactory bulb	UBERON:0002264	48.92	gold quality
myocardium	UBERON:0002349	48.87	gold quality
type B pancreatic cell	CL:0000169	48.83	gold quality
cardiac muscle of right atrium	UBERON:0003379	48.55	gold quality
CA1 field of hippocampus	UBERON:0003881	48.50	gold quality
vastus lateralis	UBERON:0001379	48.25	gold quality
left ventricle myocardium	UBERON:0006566	48.24	gold quality
orbitofrontal cortex	UBERON:0004167	48.20	gold quality
upper arm skin	UBERON:0004263	48.06	gold quality
cervix epithelium	UBERON:0004801	48.04	gold quality
oviduct epithelium	UBERON:0004804	48.00	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	3.10
E-MTAB-7303	no	7.59

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): REST

miRNA regulators (miRDB)

17 targeting GLRA1, 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-32-5P	99.98	75.21	1964
HSA-MIR-92A-3P	99.98	75.21	1960
HSA-MIR-92B-3P	99.98	75.25	1955
HSA-MIR-25-3P	99.98	74.60	1817
HSA-MIR-363-3P	99.98	74.72	1821
HSA-MIR-367-3P	99.98	74.83	1819
HSA-MIR-1236-3P	99.94	68.04	1695
HSA-MIR-3678-3P	99.31	67.10	1432
HSA-MIR-5589-3P	99.29	68.30	1443
HSA-MIR-1273H-3P	99.29	67.55	980
HSA-MIR-10B-3P	99.04	66.98	988
HSA-MIR-6895-3P	98.79	65.69	996
HSA-MIR-1914-5P	97.83	66.21	807
HSA-MIR-1279	97.83	67.50	1898
HSA-MIR-7112-3P	97.67	68.77	948
HSA-MIR-4330	95.44	66.39	993
HSA-MIR-4474-5P	94.23	67.95	568

Literature-anchored findings (GeneRIF, showing 40)

• quaternary structure of receptor fragment (PMID:11580237)
• Sequencing analysis of all exons of the alpha1 subunit of the glycine receptor (GLRA1) gene revealed a G1158A base transition in affected, heterozygous patients. (PMID:11781706)
• A novel recessive hyperekplexia allele GLRA1 (S231R): genotyping by MALDI-TOF mass spectrometry and functional characterisation (PMID:11973623)
• A single substitution at the intracellular mouth of the alpha 1 glycine receptor M2 domain converts the channel charge selectivity to cations over anions, providing evidence of critical electrostatic interactions between permeating ions and pore residues. (PMID:11981020)
• Ion charge selectivity mutation of the alpha 1 homomeric glycine receptor inverts the electrostatic profile of the channel pore by introducing a negatively charged ring at the putative selectivity filter. (PMID:11981021)
• Probing the topology of the glycine receptor alpha1 by chemical modification coupled to mass spectrometry. (PMID:11994009)
• NMR of GLRA1 reveals a pore architecture in which simultaneous tilting movements of entire TM2 helices by a mere 10 degrees may be sufficient to account for the channel gating (PMID:12080117)
• variations in glycine receptor alpha1(GlyR) density during cluster formation result from a change in GlyR efficiency due to modifications in their desensitization properties. (PMID:12237328)
• Results provide evidence for a conserved pore opening mechanism in anion-selective members of the ligand-gated ion channel family, including glycine receptors (GlyR) and gamma-aminobutyric acid, type A receptors (GABA(A)R). (PMID:12239220)
• Effects of phosphorylation on glycine receptor kinetics. with phosphorylators or with phosphatases. Phosphorylation accelerated desensitisation, but slowed deactivation and recovery from desensitisation. (PMID:12356883)
• Treatment of the glycine receptor alpha 1 channel with ginsenoside Rf enhances glycine-induced inward peak current (IGly) in a dose dependent and reversible manner but ginsenoside Rf itself did not elicit membrane currents. (PMID:12661758)
• We propose a kinetic scheme with three independent open states, where the opening rates are dependent upon the activating agonist, while the closing rates are an intrinsic characteristic of the receptor. (PMID:12679369)
• binding of zinc at the interface between adjacent glycine receptor alpha1 subunits could restrict intersubunit movements, providing a feasible mechanism for the inhibition of channel activation by zinc (PMID:12740384)
• novel GLRA1 mutation, occurring de novo in a patient with hyperekplexia, which results in the substitution of the arginine at position 218 with a glutamine (R218Q) (PMID:12746425)
• findings indicate that pressure directly and selectively antagonizes ethanol potentiation of alpha(1)glycine receptor function (PMID:12766618)
• a highly conserved aspartic acid residue in the signature disulfide loop of the alpha 1 subunit is a determinant of gating in the glycine receptor (PMID:12826676)
• We produced knock-in mice bearing the human GlyR alpha1 S267Q dominant-negative point mutation in GlyR, disrupting normal function and producing a more dramatic phenotype than the corresponding recessive null mutation (PMID:12954867)
• loops 2 and 7 in the extracellular domain play an important role in the mechanism of activation of the glycine receptor although not by a direct electrostatic mechanism (PMID:14525990)
• proton modulation of glycine receptor function is determined by extracellular domain in both the alpha1 and beta subunits (PMID:14563849)
• distinct functional characteristics of the full-length GlyR are retained in the isolated N-terminal domain. (PMID:14593111)
• Stoichiometry of recombinant heteromeric glycine receptors is revealed by a pore-lining region point mutation (PMID:14698963)
• analysis of taurine- and glycine-induced conformational changes in the M2-M3 domain of the glycine receptor (PMID:14981077)
• Effects of 12 times normal atmospheric pressure of helium-oxygen gas (pressure) on ethanol-induced potentiation of GlyR function in Xenopus oocytes expressing human alpha1, alpha2 or the mutant alpha1(A52S) GlyRs were measured by voltage clamp technics (PMID:15147510)
• Alanine-scanning mutagenesis of the residues between C138 and C152 of the Cys loop of the glycine receptor alpha 1 subunit is used to identify residues critical for receptor activation and allosteric modulation. (PMID:15287733)
• 2 novel mutations, W96C and R344X, which are located in exon 4 and exon 7 of the GLRA1 gene, were identified in a Taiwanese family with autosomal recessive hyperekplexia. (PMID:15365143)
• The architecture of the inhibitory glycine receptor alpha 1 subunit transmembrane 1-2 loop is a critical determinant of ion channel conductance and receptor desensitization. (PMID:15489161)
• Three novel mutations were identified in the GLRA1 gene associated with hereditary hyperekplexia. (PMID:15771552)
• models of the open pore structure and current-voltage characteristics of the human alpha1 GlyR second transmembrane segment (PMID:15951389)
• This study suggests that Hys-100 could exhibit incomplete penetrance, but was linked to a severe classical form of hyperekplexia in homozygous. (PMID:16078201)
• the M2-M3 loop of the glycine receptor alpha 1 responds differently to the occupation of different binding sites (PMID:16109711)
• The molecular basis for the differential sensitivity of GlyR alpha(1) and GlyR alpha(2) to Zn(2+) potentiation is reported. (PMID:16144831)
• glycine receptor function is enhanced by drug binding to a single subunit in the receptor pentamer (PMID:16361257)
• The study describe six patients from two consanguineous families with a homozygous deletion of the first seven GLRA1 exons and provide evidence of a founder effect in Kurds from Turkey (PMID:16832093)
• Microdeletion breakpoint in a GLRA1 null allele of Turkish hyperekplexia patients was identified, suggesting a founder mutation in an ethnic population originating from Turkey. (PMID:16941485)
• analysis of the sites for G protein betagamma subunit modulation on GlyRs (PMID:17040914)
• N102 is required for tropisetron inhibition of the GLRA1 subunit but not potentiation and inhibitory tropisetron binds in different orientations at different subunit interfaces. (PMID:17181559)
• Our observations suggest a novel mechanism whereby subunit specific changes in the NMDA receptor complex may be linked to chronic anxiety in AD via effects on GlyRS function. (PMID:17433503)
• data suggest that the TM2-TM3 extracellular loop plays a role in the transduction of signals generated by allosteric modulators in addition to gating signals that follow glycine binding (PMID:17434460)
• Model channels built on non-alpha chains have a constriction either near the intracellular mouth or more centrally located in the pore domain. (PMID:17469203)
• This study reports the identification of a novel Y228C mutation within the M1 trans-membrane domain of the GLRA1 subunit of the glycine receptor responsible for a severe recessive hyperekplexia phenotype in a Kurdish pedigree. (PMID:17534957)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	glra1	ENSDARG00000012019
mus_musculus	Glra1	ENSMUSG00000000263
rattus_norvegicus	Glra1	ENSRNOG00000013588

Paralogs (45): GABRA3 (ENSG00000011677), GABRA1 (ENSG00000022355), CHRNA3 (ENSG00000080644), GABRP (ENSG00000094755), CHRNA4 (ENSG00000101204), GLRA2 (ENSG00000101958), GABRE (ENSG00000102287), CHRNE (ENSG00000108556), GABRA4 (ENSG00000109158), GLRB (ENSG00000109738), GABRR2 (ENSG00000111886), GABRG2 (ENSG00000113327), CHRNB4 (ENSG00000117971), CHRNA2 (ENSG00000120903), CHRNA10 (ENSG00000129749), CHRND (ENSG00000135902), CHRNA1 (ENSG00000138435), GLRA3 (ENSG00000145451), GABRA6 (ENSG00000145863), GABRB2 (ENSG00000145864), 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 alpha-1 — P23415 (reviewed: P23415)

Alternative names: Glycine receptor 48 kDa subunit, Glycine receptor strychnine-binding subunit

All UniProt accessions (2): E5RJ70, P23415

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. Channel activity is potentiated by ethanol. Potentiation of channel activity by intoxicating levels of ethanol contribute to the sedative effects of ethanol.

Subunit / interactions. Interacts with GLRB to form heteropentameric channels; this is probably the predominant form in vivo. Heteropentamer composed of four GLRA1 subunits and one GLRB subunit. Heteropentamer composed of two GLRA1 and three GLRB. Heteropentamer composed of three GLRA1 and two GLRB. Homopentamer (in vitro). Both homopentamers and heteropentamers form functional ion channels, but their characteristics are subtly different.

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

Disease relevance. Hyperekplexia 1 (HKPX1) [MIM:149400] 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. Channel characteristics depend on the subunit composition; heteropentameric channels are activated by lower glycine levels and display faster desensitization. Channel opening is also triggered by taurine and beta-alanine. Channel activity is potentiated by nanomolar concentrations of Zn(2+); half-maximal activation is observed with 37 nM Zn(2+). Inhibited by higher Zn(2+) levels; haf-maximal inhibition occurs at 20 uM Zn(2+). Inhibited by strychnine. Strychnine binding locks the channel in a closed conformation and prevents channel opening in response to extracellular glycine. Inhibited by lindane. Inhibited by picrotoxin.

Domain organisation. The channel pore is formed by pentameric assembly of the second transmembrane domain from all five subunits. In the absence of the extracellular domain, the channel is in a constitutively open conformation. Channel opening is effected by an outward rotation of the transmembrane domains that increases the diameter of the pore.

Miscellaneous. The alpha subunit binds strychnine.

Similarity. Belongs to the ligand-gated ion channel (TC 1.A.9) family. Glycine receptor (TC 1.A.9.3) subfamily. GLRA1 sub-subfamily.

Isoforms (2)

UniProt ID	Names	Canonical?
P23415-1	a	yes
P23415-2	b

RefSeq proteins (3): NP_000162, NP_001139512, NP_001278929 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR006028	GABAA/Glycine_rcpt	Family
IPR006029	Neurotrans-gated_channel_TM	Domain
IPR006201	Neur_channel	Family
IPR006202	Neur_chan_lig-bd	Domain
IPR008127	Glycine_rcpt_A	Family
IPR008128	Glycine_rcpt_A1	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

Pfam: PF02931, PF02932

Catalyzed reactions (Rhea), 1 shown:

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

UniProt features (70 total): sequence variant 18, helix 12, mutagenesis site 9, binding site 7, topological domain 5, turn 5, transmembrane region 4, disulfide bond 2, sequence conflict 2, signal peptide 1, chain 1, region of interest 1, site 1, glycosylation site 1, splice variant 1

Structure

Experimental structures (PDB)

9 structures.

PDB	Method	Resolution (Å)
4X5T	X-RAY DIFFRACTION	3.5
8DN3	ELECTRON MICROSCOPY	3.55
8DN5	ELECTRON MICROSCOPY	3.63
8DN2	ELECTRON MICROSCOPY	3.9
8DN4	ELECTRON MICROSCOPY	4.1
1MOT	SOLUTION NMR
1VRY	SOLUTION NMR
2M6B	SOLUTION NMR
2M6I	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P23415-F1	84.48	0.61

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): 289 (important for obstruction of the ion pore in the closed conformation)

Ligand- & substrate-binding residues (7): 93; 157; 220; 222; 230–235; 232; 243

Disulfide bonds (2): 166–180, 226–237

Glycosylation sites (1): 66

Mutagenesis-validated functional residues (9):

Position	Phenotype
80	the mutant channel requires much higher glycine concentrations for activation.
137	abolishes sensitivity of channel activity to potentiation or inhibition by zn(2+); when associated with k-222.
137	strongly decreases sensitivity to inhibition by zn(2+).
220	abolishes potentiation of channel activity by zn(2+).
222	abolishes potentiation of channel activity by zn(2+).
222	abolishes sensitivity of channel activity to potentiation or inhibition by zn(2+); when associated with f-137.
243	strongly decreases potentiation of channel activity by zn(2+).
282	increased single-channel conductance. no effect on glycine sensitivity, but decreased rate of activation.
304	decreases channel conductance; the mutant channel requires much higher glycine concentrations for activation.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

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

MSigDB gene sets: 269 (showing top): GOBP_SINGLE_FERTILIZATION, GOBP_RESPONSE_TO_ETHANOL, GOBP_POSITIVE_REGULATION_OF_REPRODUCTIVE_PROCESS, MODULE_328, GOBP_RESPIRATORY_GASEOUS_EXCHANGE_BY_RESPIRATORY_SYSTEM, GOBP_RESPONSE_TO_ZINC_ION, GOBP_BEHAVIOR, GOBP_RESPONSE_TO_ACID_CHEMICAL, GOBP_ADULT_BEHAVIOR, SP3_Q3, MODULE_64, GOBP_REGULATION_OF_RESPIRATORY_SYSTEM_PROCESS, GOCC_CELL_SURFACE, GOBP_NEGATIVE_REGULATION_OF_NERVOUS_SYSTEM_PROCESS, GOBP_RESPIRATORY_SYSTEM_PROCESS

GO Biological Process (28): startle response (GO:0001964), regulation of respiratory gaseous exchange by nervous system process (GO:0002087), monoatomic ion transport (GO:0006811), chloride transport (GO:0006821), muscle contraction (GO:0006936), neuropeptide signaling pathway (GO:0007218), acrosome reaction (GO:0007340), visual perception (GO:0007601), adult walking behavior (GO:0007628), neuronal action potential (GO:0019228), regulation of membrane potential (GO:0042391), neuromuscular process controlling posture (GO:0050884), negative regulation of transmission of nerve impulse (GO:0051970), synaptic transmission, glycinergic (GO:0060012), righting reflex (GO:0060013), inhibitory postsynaptic potential (GO:0060080), cellular response to amino acid stimulus (GO:0071230), cellular response to zinc ion (GO:0071294), cellular response to ethanol (GO:0071361), response to alcohol (GO:0097305), chloride transmembrane transport (GO:1902476), positive regulation of acrosome reaction (GO:2000344), chemical synaptic transmission (GO:0007268), monoatomic ion transmembrane transport (GO:0034220), regulation of respiratory gaseous exchange (GO:0043576), neuromuscular process (GO:0050905), excitatory postsynaptic potential (GO:0060079), regulation of presynaptic membrane potential (GO:0099505)

GO Molecular Function (15): transmembrane signaling receptor activity (GO:0004888), excitatory extracellular ligand-gated monoatomic ion channel activity (GO:0005231), zinc ion binding (GO:0008270), glycine binding (GO:0016594), extracellularly glycine-gated chloride channel activity (GO:0016934), taurine binding (GO:0030977), identical protein binding (GO:0042802), ligand-gated monoatomic ion channel activity involved in regulation of presynaptic membrane potential (GO:0099507), 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), transmitter-gated monoatomic ion channel activity (GO:0022824), metal ion binding (GO:0046872)

GO Cellular Component (14): plasma membrane (GO:0005886), external side of plasma membrane (GO:0009897), membrane (GO:0016020), dendrite (GO:0030425), chloride channel complex (GO:0034707), neuron projection (GO:0043005), neuronal cell body (GO:0043025), perikaryon (GO:0043204), intracellular membrane-bounded organelle (GO:0043231), synapse (GO:0045202), postsynaptic membrane (GO:0045211), inhibitory synapse (GO:0060077), glycinergic synapse (GO:0098690), cell projection (GO:0042995)

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
neuromuscular process	2
transmission of nerve impulse	2
regulation of postsynaptic membrane potential	2
extracellular ligand-gated monoatomic ion channel activity	2
cation binding	2
ligand-gated monoatomic ion channel activity	2
synapse	2
response to external stimulus	1
respiratory gaseous exchange by respiratory system	1
regulation of respiratory system process	1
nervous system process	1
transport	1
monoatomic anion transport	1
inorganic anion transport	1
muscle system process	1
G protein-coupled receptor signaling pathway	1
membrane fusion involved in acrosome reaction	1
single fertilization	1
reproductive process	1
acrosomal vesicle exocytosis	1
sensory perception of light stimulus	1
adult locomotory behavior	1
walking behavior	1
action potential	1
monoatomic ion transmembrane transport	1
regulation of biological quality	1
musculoskeletal movement	1
negative regulation of cell communication	1
negative regulation of nervous system process	1
regulation of transmission of nerve impulse	1
chemical synaptic transmission	1
reflex	1
chemical synaptic transmission, postsynaptic	1
response to amino acid	1
cellular response to acid chemical	1
response to zinc ion	1
cellular response to metal ion	1
response to ethanol	1
cellular response to alcohol	1

Protein interactions and networks

STRING

882 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
GLRA1	SLC6A5	Q9Y345	950
GLRA1	GPHN	Q9NQX3	900
GLRA1	ARHGEF9	O43307	809
GLRA1	DPYSL5	Q9BPU6	785
GLRA1	GARS1	P41250	728
GLRA1	AMPH	P49418	668
GLRA1	IL12A	P29459	637
GLRA1	GAD2	Q05329	609
GLRA1	SDCBP	O00560	602
GLRA1	BIN1	O00499	570
GLRA1	TRAK1	Q9UPV9	504
GLRA1	GRIN3A	Q8TCU5	498
GLRA1	CHRM3	P20309	497
GLRA1	IL12B	P29460	491
GLRA1	CHRM2	P08172	491

IntAct

10 interactions, top by confidence:

A	B	Type	Score
GLRA1	MAGED1	psi-mi:“MI:0915”(physical association)	0.560
SORBS3	GLRA1	psi-mi:“MI:0915”(physical association)	0.560
GLRA1	GLRB	psi-mi:“MI:0915”(physical association)	0.400
SLC22A23	NRP1	psi-mi:“MI:0914”(association)	0.350
GLRA1	SORBS3	psi-mi:“MI:0915”(physical association)	0.000
GLRA1	MAGED1	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (5): GLRA1 (Two-hybrid), MAGED1 (Two-hybrid), GLRA1 (Negative Genetic), GLRA1 (Affinity Capture-MS), GLRA1 (Affinity Capture-RNA)

ESM2 similar proteins: A8MPY1, F1R8P4, O75311, O93430, P02713, P02714, P02715, P02716, P02717, P02718, P04759, P05376, P09628, P09660, P09690, P20782, P22770, P22771, P23415, P23416, P24046, P24524, P25110, P26714, P28476, P43144, P47742, P49580, P49582, P50572, P50573, P54244, P56475, P56476, P57695, Q05941, Q07001, Q08832, Q0II76, Q24352

Diamond homologs: A8MPY1, D1LYT2, F1R8P4, G5EBR3, O00591, O09028, O14764, O18276, O75311, O93430, P07727, P08219, P08220, P0C2W5, P10063, P10064, P14867, P15431, P16305, P18505, P18506, P18507, P18508, P19019, P19150, P19969, P20236, P20237, P20781, P21548, P22300, P22723, P22771, P22933, P23415, P23416, P23574, P23576, P24045, P24046

SIGNOR signaling

5 interactions.

A	Effect	B	Mechanism
taurine	“up-regulates activity”	GLRA1	“chemical activation”
glycine	“up-regulates activity”	GLRA1	“chemical activation”
beta-alanine	“up-regulates activity”	GLRA1	“chemical activation”
ethanol	“up-regulates activity”	GLRA1	“chemical activation”

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	50
Likely pathogenic	27
Uncertain significance	252
Likely benign	177
Benign	31

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1070761	NM_000171.4(GLRA1):c.634_635del (p.Leu212fs)	Pathogenic
1076337	NC_000005.9:g.(?151266262)(151266369_?)del	Pathogenic
1076338	NC_000005.9:g.(?151239326)(151239589_?)del	Pathogenic
1299007	NM_000171.4(GLRA1):c.942G>A (p.Trp314Ter)	Pathogenic
1323021	NM_000171.4(GLRA1):c.675C>A (p.Tyr225Ter)	Pathogenic
1373698	NM_000171.4(GLRA1):c.376del (p.Leu126fs)	Pathogenic
1431352	NM_000171.4(GLRA1):c.378del (p.Phe127fs)	Pathogenic
1436466	NM_000171.4(GLRA1):c.1101T>A (p.Tyr367Ter)	Pathogenic
1459155	NM_000171.4(GLRA1):c.895C>T (p.Arg299Ter)	Pathogenic
16061	NM_000171.4(GLRA1):c.896G>A (p.Arg299Gln)	Pathogenic
16062	NM_000171.4(GLRA1):c.815T>A (p.Ile272Asn)	Pathogenic
16063	NM_000171.4(GLRA1):c.920A>G (p.Tyr307Cys)	Pathogenic
16064	NM_000171.4(GLRA1):c.882G>C (p.Gln294His)	Pathogenic
16065	NM_000171.4(GLRA1):c.910A>G (p.Lys304Glu)	Pathogenic
16066	NM_000171.4(GLRA1):c.832C>A (p.Pro278Thr)	Pathogenic
16069	NM_000171.4(GLRA1):c.690C>A (p.Tyr230Ter)	Pathogenic
16071	NM_000171.4(GLRA1):c.777C>G (p.Ser259Arg)	Pathogenic
16072	NM_001146040.1(GLRA1):c.(?-287)(912+?)del	Pathogenic
16073	NM_000171.4(GLRA1):c.971C>A (p.Ser324Ter)	Pathogenic
16074	NM_000171.4(GLRA1):c.884G>A (p.Ser295Asn)	Pathogenic
1705885	GRCh37/hg19 5q33.1(chr5:151264215-151547865)x0	Pathogenic
2014746	NM_000171.4(GLRA1):c.258_260del (p.Tyr86_Arg87delinsTer)	Pathogenic
2045456	NM_000171.4(GLRA1):c.381dup (p.Phe128fs)	Pathogenic
2136350	NM_000171.4(GLRA1):c.278G>T (p.Arg93Leu)	Pathogenic
2162119	NM_000171.4(GLRA1):c.537dup (p.Cys180fs)	Pathogenic
2196359	NM_000171.4(GLRA1):c.298C>T (p.Arg100Cys)	Pathogenic
2422534	NC_000005.9:g.(?151230931)(151304110_?)del	Pathogenic
2422535	NC_000005.9:g.(?151304035)(151304110_?)del	Pathogenic
2756322	NM_000171.4(GLRA1):c.725del (p.Phe242fs)	Pathogenic
2778873	NM_000171.4(GLRA1):c.99dup (p.Lys34fs)	Pathogenic

SpliceAI

1467 predictions. Top by Δscore:

Variant	Effect	Δscore
5:151828916:CCTA:C	donor_loss	1.0000
5:151828919:A:C	donor_loss	1.0000
5:151828920:C:A	donor_loss	1.0000
5:151851385:CTTA:C	donor_loss	1.0000
5:151851386:TTACC:T	donor_loss	1.0000
5:151851387:TA:T	donor_loss	1.0000
5:151851388:A:AC	donor_gain	1.0000
5:151851388:ACCT:A	donor_loss	1.0000
5:151851389:C:CC	donor_gain	1.0000
5:151851605:C:A	acceptor_loss	1.0000
5:151855173:TCCAA:T	acceptor_gain	1.0000
5:151855174:CCAA:C	acceptor_gain	1.0000
5:151855174:CCAAC:C	acceptor_gain	1.0000
5:151855175:CAA:C	acceptor_gain	1.0000
5:151855175:CAAC:C	acceptor_gain	1.0000
5:151855178:C:CC	acceptor_gain	1.0000
5:151856299:A:AC	donor_gain	1.0000
5:151856300:C:CC	donor_gain	1.0000
5:151856300:CAG:C	donor_gain	1.0000
5:151859781:TCACC:T	donor_loss	1.0000
5:151859783:A:AC	donor_gain	1.0000
5:151859784:C:CT	donor_gain	1.0000
5:151859784:CCTG:C	donor_gain	1.0000
5:151859784:CCTGA:C	donor_gain	1.0000
5:151860004:TAGTC:T	acceptor_gain	1.0000
5:151860016:C:CT	acceptor_gain	1.0000
5:151860016:C:T	acceptor_gain	1.0000
5:151860017:A:T	acceptor_gain	1.0000
5:151892434:CAAGG:C	acceptor_gain	1.0000
5:151892439:C:CC	acceptor_gain	1.0000

AlphaMissense

2990 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
5:151822720:A:G	W443R	1.000
5:151822720:A:T	W443R	1.000
5:151822742:G:C	F435L	1.000
5:151822742:G:T	F435L	1.000
5:151822744:A:G	F435L	1.000
5:151822754:G:C	F431L	1.000
5:151822754:G:T	F431L	1.000
5:151822756:A:G	F431L	1.000
5:151822776:T:A	D424V	1.000
5:151822776:T:G	D424A	1.000
5:151822777:C:G	D424H	1.000
5:151822788:G:T	A420D	1.000
5:151828981:G:C	N333K	1.000
5:151828981:G:T	N333K	1.000
5:151828985:A:T	V332D	1.000
5:151828988:G:T	A331D	1.000
5:151828989:C:G	A331P	1.000
5:151828991:G:T	A330D	1.000
5:151828995:A:G	Y329H	1.000
5:151828996:T:A	E328D	1.000
5:151828996:T:G	E328D	1.000
5:151828998:C:T	E328K	1.000
5:151829003:A:G	L326P	1.000
5:151829006:G:T	A325D	1.000
5:151829011:G:C	F323L	1.000
5:151829011:G:T	F323L	1.000
5:151829013:A:G	F323L	1.000
5:151829024:A:G	L319P	1.000
5:151829026:G:C	C318W	1.000
5:151829027:C:T	C318Y	1.000

dbSNP variants (sampled 300 via entrez): RS1000009053 (5:151919479 C>T), RS1000031723 (5:151863481 C>A,T), RS1000040208 (5:151919124 T>C), RS1000080433 (5:151863191 C>T), RS1000103776 (5:151868823 T>C), RS1000126917 (5:151908414 G>T), RS1000168011 (5:151843242 C>G,T), RS1000225452 (5:151891989 T>C), RS1000255967 (5:151850274 C>T), RS1000282821 (5:151836308 G>A,T), RS1000289608 (5:151895631 G>C), RS1000379296 (5:151925250 C>G,T), RS1000383668 (5:151895827 G>A), RS1000447404 (5:151896509 A>C,T), RS1000449671 (5:151875465 C>A,T)

Disease associations

OMIM: gene MIM:138491 | disease phenotypes: MIM:149400

GenCC curated gene-disease

Disease	Classification	Inheritance
hyperekplexia 1	Definitive	Autosomal dominant
hereditary hyperekplexia	Supportive	Autosomal dominant

Mondo (2): hereditary hyperekplexia (MONDO:0021022), hyperekplexia 1 (MONDO:0007868)

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

HPO phenotypes

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

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000023	Inguinal hernia
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001251	Ataxia
HP:0001257	Spasticity
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:0002104	Apnea
HP:0002267	Exaggerated startle response
HP:0002359	Frequent falls
HP:0002360	Sleep disturbance
HP:0002375	Hypokinesia
HP:0002380	Fasciculations
HP:0002827	Hip dislocation
HP:0002835	Aspiration
HP:0003552	Muscle stiffness
HP:0003593	Infantile onset
HP:0031951	Nocturnal seizures
HP:0100022	Abnormality of movement
HP:0100633	Esophagitis

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST007565_66	Morning person	9.000000e-14

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0008328	chronotype measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL2363052 (PROTEIN COMPLEX), CHEMBL5845 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

15 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 2,107,511 (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
CHEMBL1017	TELMISARTAN	4	27,457
CHEMBL1042	CHOLECALCIFEROL	4	64,162
CHEMBL1200969	DUTASTERIDE	4	11,156
CHEMBL1201284	CINACALCET	4	5,917
CHEMBL1265	ADAPALENE	4	12,179
CHEMBL1423	PIMOZIDE	4	17,310
CHEMBL15770	SULINDAC	4	80,712
CHEMBL1946170	REGORAFENIB	4	12,678
CHEMBL296419	ASTEMIZOLE	4	21,577
CHEMBL416956	MEFLOQUINE	4	15,549
CHEMBL465	DRONABINOL	4	62,107
CHEMBL46516	FLUSPIRILENE	4	41,239
CHEMBL773	GLYCINE	4	1,220,071
CHEMBL85	RISPERIDONE	4	41,869
CHEMBL1232863	FRUCTOSE	2	473,528

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

GtoPdb / IUPHAR curated pharmacology

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

Target class: lgic — Glycine receptors

Most potent curated ligand interactions (16 total), top 16:

Ligand	Action	Affinity	Parameter
anandamide	Potentiation	7.4	pEC50
HU-210	Potentiation	6.6	pEC50
ginkgolide B	Channel blocker	6.2	pIC50
ginkgolide X	Antagonist	6.1	pIC50
cyanotriphenylborate	Channel blocker	5.9	pIC50
pregnenolone sulphate	Antagonist	5.7	pKi
Δ9-tetrahydrocannabinol	Potentiation	5.5	pEC50
nifedipine	Antagonist	5.5	pIC50
Cu2+	Inhibition	5.4	pIC50
picrotoxinin	Channel blocker	5.3	pIC50
picrotin	Channel blocker	5.3	pIC50
picrotoxin	Channel blocker	5.2	pIC50
Zn2+	Inhibition	4.8	pIC50
bilobalide	Antagonist	4.7	pIC50
tropisetron	Antagonist	4.1	pKi
colchicine	Antagonist	3.5	pIC50

Binding affinities (BindingDB)

5 measured of 5 human assays (6 total across all organisms); most potent 5 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
4-hydroxy-3,5-di(propan-2-yl)benzoic acid	EC50	0.00016 nM	US-9676786: Pharmacologically active compounds
[4-hydroxy-3,5-di(propan-2-yl)phenyl]-(4-methylpiperazin-1-yl)methanone	EC50	0.0012 nM	US-9676786: Pharmacologically active compounds
4-phenylmethoxy-3,5-di(propan-2-yl)benzoyl chloride	EC50	0.06 nM	US-9676786: Pharmacologically active compounds
(3-fluoroazetidin-1-yl)-[4-phenylmethoxy-3,5-di(propan-2-yl)phenyl]methanone	EC50	0.43 nM	US-9676786: Pharmacologically active compounds
Gelsemine	IC50	30000 nM

ChEMBL bioactivities

306 potent at pChembl≥5 of 332 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
10.22	EC50	0.06	nM	CHEMBL4228372
10.22	EC50	0.06	nM	CHEMBL5912281
9.37	EC50	0.43	nM	CHEMBL4227297
9.37	EC50	0.43	nM	CHEMBL6045267
8.30	Ki	5	nM	STRYCHNINE
7.80	EC50	16	nM	CHEMBL4070615
7.64	Ki	23	nM	STRYCHNINE
7.57	IC50	27	nM	STRYCHNINE
7.50	EC50	32	nM	CHEMBL4070615
7.40	Ki	40	nM	CHEMBL4089150
7.37	IC50	43	nM	CHEMBL4103909
7.34	IC50	46	nM	CHEMBL4079657
7.31	IC50	49	nM	CHEMBL4079657
7.30	IC50	50	nM	STRYCHNINE
7.29	IC50	51.29	nM	CHEMBL4103909
7.29	IC50	51	nM	STRYCHNINE
7.28	IC50	52	nM	CHEMBL4103909
7.26	IC50	55	nM	CHEMBL4865147
7.25	IC50	56	nM	CHEMBL4102677
7.24	IC50	58	nM	STRYCHNINE
7.23	IC50	59	nM	CHEMBL4103909
7.22	IC50	60	nM	STRYCHNINE
7.17	Ki	67	nM	CHEMBL4096857
7.17	IC50	67	nM	CHEMBL4855686
7.12	IC50	76	nM	CHEMBL4060962
7.12	IC50	75	nM	CHEMBL4102677
7.11	IC50	77.62	nM	CHEMBL4060962
7.11	IC50	77	nM	CHEMBL4060962
7.10	IC50	80	nM	CHEMBL4089150
7.09	IC50	82	nM	CHEMBL4089150
7.09	Ki	81	nM	CHEMBL4865147
7.05	IC50	90	nM	CHEMBL4849489
7.04	Ki	91	nM	CHEMBL4518537
7.03	IC50	93.33	nM	STRYCHNINE
7.03	IC50	93	nM	STRYCHNINE
7.02	IC50	95.5	nM	CHEMBL4079657
7.02	IC50	95	nM	CHEMBL4079657
7.01	IC50	97.72	nM	CHEMBL4089150
7.01	IC50	97	nM	CHEMBL4089150
7.01	IC50	97	nM	CHEMBL4060962
7.00	IC50	100	nM	CHEMBL4102677
7.00	IC50	100	nM	CHEMBL4870499
6.98	IC50	104.7	nM	CHEMBL4102677
6.96	IC50	110	nM	CHEMBL4068867
6.96	IC50	109	nM	CHEMBL4068867
6.94	IC50	114.8	nM	CHEMBL4068867
6.94	IC50	116	nM	CHEMBL4068867
6.91	Ki	123	nM	STRYCHNINE
6.89	IC50	130	nM	CHEMBL4857611
6.87	IC50	134	nM	STRYCHNINE

PubChem BioAssay actives

306 with measured affinity, of 492 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
[4-hydroxy-3,5-di(propan-2-yl)phenyl]-(4-methylpiperazin-1-yl)methanone	1388384: Positive allosteric modulation of GlyRalpha1 (unknown origin) assessed as potentiation of glycine-induced response	ec50	<0.0001	uM
[4-hydroxy-3,5-di(propan-2-yl)phenyl]-(2-oxa-6-azaspiro[3.3]heptan-6-yl)methanone	1388384: Positive allosteric modulation of GlyRalpha1 (unknown origin) assessed as potentiation of glycine-induced response	ec50	<0.0001	uM
[4-hydroxy-3,5-di(propan-2-yl)phenyl]-[(2R)-2-methylmorpholin-4-yl]methanone	1388384: Positive allosteric modulation of GlyRalpha1 (unknown origin) assessed as potentiation of glycine-induced response	ec50	0.0001	uM
(3-fluoroazetidin-1-yl)-[4-hydroxy-3,5-di(propan-2-yl)phenyl]methanone	1388384: Positive allosteric modulation of GlyRalpha1 (unknown origin) assessed as potentiation of glycine-induced response	ec50	0.0004	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	1761887: Displacement of [3H]strychnine from human glycine receptor subunit alpha-1 expressed in HEK293 cell membranes preincubated for 30 mins followed by [3H]strychnine addition and measured after 30 mins by liquid scintillation counting method	ki	0.0050	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-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	1431422: Displacement of [3H]strychnine from recombinant human glycine receptor alpha 1 expressed in HEK293 cell membranes after 30 mins by liquid scintillation counting method	ki	0.0400	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
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	1761889: Antagonist activity at human glycine receptor subunit alpha-1 assessed as inhibition of glycine-induced current measured at the later state of compound application by patch-clamp assay	ic50	0.0550	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
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	1761889: Antagonist activity at human glycine receptor subunit alpha-1 assessed as inhibition of glycine-induced current measured at the later state of compound application by patch-clamp assay	ic50	0.0670	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	1431422: Displacement of [3H]strychnine from recombinant human glycine receptor alpha 1 expressed in HEK293 cell membranes after 30 mins by liquid scintillation counting method	ki	0.0670	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	1431419: Antagonist activity at recombinant human glycine receptor alpha 1 expressed in HEK293 cells assessed as inhibition of glycine-induced current at -50 mV holding potential by whole cell patch-clamp method	ic50	0.0760	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	1761885: Antagonist activity at human glycine receptor subunit alpha-1 expressed in HEK293 cells assessed as reduction in glycine-induced currents by whole-cell patch-clamp assay	ic50	0.0900	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	1545112: Displacement of [3H]strychnine from human glycine receptor subunit alpha-1 expressed in HEK293 cell membranes	ki	0.0910	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	1761885: Antagonist activity at human glycine receptor subunit alpha-1 expressed in HEK293 cells assessed as reduction in glycine-induced currents by whole-cell patch-clamp assay	ic50	0.1000	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	1431419: Antagonist activity at recombinant human glycine receptor alpha 1 expressed in HEK293 cells assessed as inhibition of glycine-induced current at -50 mV holding potential by whole cell patch-clamp method	ic50	0.1090	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	1761885: Antagonist activity at human glycine receptor subunit alpha-1 expressed in HEK293 cells assessed as reduction in glycine-induced currents by whole-cell patch-clamp assay	ic50	0.1300	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-methoxyethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]propanoylamino]pentanamide	1761889: Antagonist activity at human glycine receptor subunit alpha-1 assessed as inhibition of glycine-induced current measured at the later state of compound application by patch-clamp assay	ic50	0.1370	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-methoxyethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]propanoylamino]undecanamide	1761889: Antagonist activity at human glycine receptor subunit alpha-1 assessed as inhibition of glycine-induced current measured at the later state of compound application by patch-clamp assay	ic50	0.1580	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	1431417: Antagonist activity at recombinant human glycine receptor alpha 1 expressed in human tsA201 cells assessed as inhibition of glycine-induced receptor activation after 30 mins by FLIPR membrane potential blue assay	ic50	0.1660	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	1761885: Antagonist activity at human glycine receptor subunit alpha-1 expressed in HEK293 cells assessed as reduction in glycine-induced currents by whole-cell patch-clamp assay	ic50	0.1700	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
(4aR,5aS,8aR,13aS,15S,15aR,15bR)-15-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	1545115: Antagonist activity at human glycine receptor subunit alpha-1 expressed in HEK293 cells assessed as reduction in glycine-induced whole cell currents by patch-clamp technique	ic50	0.1940	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
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	1431417: Antagonist activity at recombinant human glycine receptor alpha 1 expressed in human tsA201 cells assessed as inhibition of glycine-induced receptor activation after 30 mins by FLIPR membrane potential blue assay	ic50	0.2200	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	1431417: Antagonist activity at recombinant human glycine receptor alpha 1 expressed in human tsA201 cells assessed as inhibition of glycine-induced receptor activation after 30 mins by FLIPR membrane potential blue assay	ic50	0.2455	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	1431417: Antagonist activity at recombinant human glycine receptor alpha 1 expressed in human tsA201 cells assessed as inhibition of glycine-induced receptor activation after 30 mins by FLIPR membrane potential blue assay	ic50	0.2600	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
Cinacalcet	1203550: Potentiation of human GlyR-alpha1 expressed in Xenopus laevis oocytes assessed as induction of glycine-activated currents after 1 to 4 days by two-electrode voltage clamp assay	ec50	0.3200	uM
Risperidone	1203550: Potentiation of human GlyR-alpha1 expressed in Xenopus laevis oocytes assessed as induction of glycine-activated currents after 1 to 4 days by two-electrode voltage clamp assay	ec50	0.3200	uM
Dutasteride	1203550: Potentiation of human GlyR-alpha1 expressed in Xenopus laevis oocytes assessed as induction of glycine-activated currents after 1 to 4 days by two-electrode voltage clamp assay	ec50	0.3300	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	1431417: Antagonist activity at recombinant human glycine receptor alpha 1 expressed in human tsA201 cells assessed as inhibition of glycine-induced receptor activation after 30 mins by FLIPR membrane potential blue assay	ic50	0.3700	uM
Sulindac	1203550: Potentiation of human GlyR-alpha1 expressed in Xenopus laevis oocytes assessed as induction of glycine-activated currents after 1 to 4 days by two-electrode voltage clamp assay	ec50	0.3800	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	1761885: Antagonist activity at human glycine receptor subunit alpha-1 expressed in HEK293 cells assessed as reduction in glycine-induced currents by whole-cell patch-clamp assay	ic50	0.4000	uM
cholecalciferol	1203550: Potentiation of human GlyR-alpha1 expressed in Xenopus laevis oocytes assessed as induction of glycine-activated currents after 1 to 4 days by two-electrode voltage clamp assay	ec50	0.4000	uM
2-[3-[(E,12S,13Z)-4-hydroxy-13-(3-hydroxy-4-methyl-5-oxofuran-2-ylidene)-4,8,12-trimethyltridec-7-enyl]-5-oxo-2H-pyrrol-1-yl]acetic acid	474942: Agonist activity at human recombinant alpha 1 GlyR expressed in HEK293 cells assessed as potentiation of glycine current by whole cell patch clamp assay	ec50	0.5000	uM
(1S,6R,8S,9R,11R,12R,13R,16S,17S)-8-tert-butyl-6,9,12-trihydroxy-16-methyl-2,4,14,19-tetraoxahexacyclo[8.7.2.01,11.03,7.07,11.013,17]nonadecane-5,15,18-trione	281248: Activity at human alpha-1-beta-GlyR expressed in HEK293 cells by FMP assay	ic50	0.5012	uM
(1’R,2’S,3S,5’S,6’S,8’R,11’S)-2’-ethenyl-4’-methylspiro[1H-indole-3,7’-9-oxa-4-azatetracyclo[6.3.1.02,6.05,11]dodecane]-2-one	1388046: Positive allosteric modulation of recombinant human glycine receptor alpha1 expressed in HEK293 cells assessed as increase in glycine-induced current at -60 mV holding potential by whole cell patch-clamp method	ec50	0.5900	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
(1R,3R,6R,7S,8S,10R,11S,13S,16S,17R)-8-tert-butyl-6,17-dihydroxy-16-methyl-2,4,14,19-tetraoxahexacyclo[8.7.2.01,11.03,7.07,11.013,17]nonadecane-5,15,18-trione	281248: Activity at human alpha-1-beta-GlyR expressed in HEK293 cells by FMP assay	ic50	0.6310	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-(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	1431417: Antagonist activity at recombinant human glycine receptor alpha 1 expressed in human tsA201 cells assessed as inhibition of glycine-induced receptor activation after 30 mins by FLIPR membrane potential blue assay	ic50	0.6900	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	1431417: Antagonist activity at recombinant human glycine receptor alpha 1 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
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	1761885: Antagonist activity at human glycine receptor subunit alpha-1 expressed in HEK293 cells assessed as reduction in glycine-induced currents by whole-cell patch-clamp assay	ic50	0.7200	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	1761883: Antagonist activity at human glycine receptor subunit alpha-1 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	0.7300	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	1761885: Antagonist activity at human glycine receptor subunit alpha-1 expressed in HEK293 cells assessed as reduction in glycine-induced currents by whole-cell patch-clamp assay	ic50	1.1000	uM
8-[4,4-bis(4-fluorophenyl)butyl]-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one	1203550: Potentiation of human GlyR-alpha1 expressed in Xenopus laevis oocytes assessed as induction of glycine-activated currents after 1 to 4 days by two-electrode voltage clamp assay	ec50	1.2000	uM
(5Z)-5-[(E,2S)-13-(furan-3-yl)-10-hydroxy-2,6,10-trimethyltridec-6-enylidene]-4-hydroxy-3-methylfuran-2-one	474942: Agonist activity at human recombinant alpha 1 GlyR expressed in HEK293 cells assessed as potentiation of glycine current by whole cell patch clamp assay	ec50	1.2000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Strychnine	increases reaction, affects binding, decreases activity	3
Glycine Agents	increases reaction, affects binding, decreases activity, affects activity, affects reaction (+1 more)	3
brucine	decreases activity, affects binding	2
Enflurane	increases activity, increases reaction	2
Glycine	affects activity, decreases reaction, affects reaction, increases activity, affects response to substance	2
Ivermectin	affects activity, affects reaction, increases activity	2
Zinc	affects binding, decreases response to substance, decreases activity	2
aristolochic acid I	increases expression	1
7alpha,8beta-dihydroxydeepoxysarcophine	increases activity, affects activity, affects reaction	1
bisphenol F	affects cotreatment, increases methylation	1
sarcophine	decreases reaction, increases activity, decreases activity	1
arsenite	increases methylation	1
pregnenolone sulfate	decreases activity	1
1,1,1-trichloroethane	increases activity, increases reaction, increases response to substance	1
n-butyl mercaptan	affects binding, decreases activity, increases reaction	1
propanethiol	affects binding, decreases activity, increases reaction	1
RU 5135	affects binding, decreases activity	1
tribromoethanol	increases activity, increases reaction	1
fipronil	decreases activity	1
3-(2’-phosphonomethyl(1,1’-biphenyl)-3-yl)alanine	affects binding, decreases activity	1
CGP 52608	affects binding, increases reaction	1
Sevoflurane	increases activity, increases reaction	1
Fulvestrant	affects cotreatment, increases methylation	1
Leflunomide	increases expression	1
Acetaldehyde	increases activity	1
Ethanol	increases activity, increases reaction	1
Butanols	affects binding, decreases activity, increases reaction	1
Atropine	decreases activity, affects binding	1
Hexachlorocyclohexane	decreases activity	1
Benzo(a)pyrene	affects methylation	1

ChEMBL screening assays

59 unique, capped per target: 51 binding, 7 functional, 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
CHEMBL1107103	Functional	Agonist activity at human recombinant alpha 1 GlyR expressed in HEK293 cells assessed as potentiation of glycine current by whole cell patch clamp assay	Ircinialactams: subunit-selective glycine receptor modulators from Australian sponges of the family Irciniidae. — Bioorg Med Chem

Cellosaurus cell lines

1 cell lines: 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D1JR	PrecisION hGlyRA1-HEK	Transformed cell line	Female

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