Affinage

GLRA1

Glycine receptor subunit alpha-1 · UniProt P23415

Length
457 aa
Mass
52.6 kDa
Annotated
2026-06-10
44 papers in source corpus 13 papers cited in narrative 13 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

GLRA1 encodes the alpha1 subunit of the inhibitory glycine receptor, a glycine-gated chloride channel that assembles as a pentamer (3 alpha1: 2 beta) and mediates fast inhibitory neurotransmission in brainstem and spinal cord motor circuits (PMID:7874121). Loss of alpha1 abolishes functional receptor activity, with no compensation by other alpha subunits, and also depletes the postsynaptic anchoring protein gephyrin, linking alpha1 to organization of the glycinergic postsynapse (PMID:7874121, PMID:9145798); in zebrafish, glra1 is non-redundantly required for inhibitory control of locomotion (PMID:31048868). The receptor is built from autonomous structural modules — the C-terminal TM3-TM4 region complements truncation mutants in trans to restore channel activity — reflecting the modular architecture of Cys-loop receptors (PMID:19244519). Dominant hyperekplexia mutations act on channel function: residues in the cytoplasmic M1-M2 loop govern current amplitude and desensitization (P250T), TM2 residue S267 forms part of the ethanol/anesthetic modulatory site, the extracellular W170 controls Zn2+ potentiation distinct from the Zn2+ inhibition site, and I244N produces a constitutive leak conductance, whereas recessive mutations predominantly cause trafficking/surface-expression defects (e.g. TM1 residue S231R) — defining two principal pathophysiological mechanisms in startle disease (PMID:9920650, PMID:18043720, PMID:24198360, PMID:20631190, PMID:11973623). Mutations and deletions of GLRA1 cause hyperekplexia (startle disease), with complete loss surviving in humans (PMID:1355335, PMID:8651283). Beyond its synaptic role, GLRA1 physically interacts with calmodulin in pancreatic beta cells to maintain ER calcium homeostasis and sustain insulin gene expression and secretion (PMID:42037784).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 1992 High

    Establishing the chromosomal locus of the startle disease gene was needed to identify the molecular cause of hyperekplexia; linkage to 5q33-q35 nominated GLRA1 as the candidate.

    Evidence Linkage analysis with polymorphic markers in a large hyperekplexia pedigree

    PMID:1355335

    Open questions at the time
    • Linkage alone did not identify causal mutations or the gene product's function
    • Did not establish receptor subunit composition
  2. 1994 High

    It was unknown whether alpha1 was strictly required for receptor function; loss-of-function in the oscillator mouse showed alpha1 is non-redundant for forming the glycine-gated chloride channel.

    Evidence Radioligand [3H]strychnine binding and genetic mapping in mouse oscillator/spasmodic mutants

    PMID:7874121

    Open questions at the time
    • Did not resolve which structural regions control gating versus trafficking
    • Stoichiometry inferred biochemically, not structurally
  3. 1997 High

    Whether alpha1 organizes the postsynaptic scaffold was unclear; complete loss of alpha1 was shown to deplete gephyrin, linking the receptor to synaptic anchoring.

    Evidence Western blot and [3H]strychnine binding in oscillator null mice

    PMID:9145798

    Open questions at the time
    • Did not define whether the alpha1-gephyrin relationship is direct or activity-dependent
    • Mechanism of gephyrin destabilization unresolved
  4. 1996 Medium

    It was unknown whether complete GLRA1 loss is survivable in humans; a homozygous exon 1-6 deletion produced non-lethal hyperekplexia with preserved inhibition, indicating partial compensation.

    Evidence Genomic deletion analysis and clinical phenotyping in a consanguineous family

    PMID:8651283

    Open questions at the time
    • Single consanguineous family
    • Compensatory mechanism not identified
  5. 1999 High

    The functional role of the cytoplasmic loop was undefined; P250T showed the M1-M2 loop determines channel gating via current amplitude and desensitization recovery.

    Evidence Recombinant expression and patch-clamp electrophysiology in HEK293 cells

    PMID:9920650

    Open questions at the time
    • Single mutation in a heterologous system
    • Synaptic consequences not measured
  6. 2002 High

    How recessive mutations cause disease was unclear; S231R in TM1 was shown to impair biogenesis and surface integration, defining a trafficking mechanism.

    Evidence Biochemistry, patch-clamp, confocal microscopy on recombinant receptors

    PMID:11973623

    Open questions at the time
    • Trafficking machinery responsible not identified
    • Single mutation analyzed
  7. 2007 Medium

    The molecular site of ethanol/anesthetic modulation was undefined; S267N abolished ethanol modulation, placing S267 in TM2 at the modulatory site.

    Evidence Recombinant expression with pharmacological modulation electrophysiology

    PMID:18043720

    Open questions at the time
    • Single lab, single study
    • Physiological relevance of ethanol site to hyperekplexia unclear
  8. 2010 High

    Whether hyperekplexia mutations fall into mechanistic classes was unresolved; systematic analysis of 13 mutations established that recessive alleles cause trafficking defects and non-trafficking alleles alter glycine sensitivity, with I244N revealing a constitutive leak mechanism.

    Evidence High-content imaging and patch-clamp of homomeric and heteromeric GlyRs in HEK293 cells

    PMID:20631190

    Open questions at the time
    • In vitro classification not validated in vivo
    • Leak conductance mechanism structurally undefined
  9. 2009 High

    Subunit architecture was poorly defined; coexpression of an isolated C-terminal TM3-TM4 module rescued channel activity in truncation mutants, demonstrating modular assembly.

    Evidence Recombinant coexpression complementation, electrophysiology, viral rescue in oscillator neurons

    PMID:19244519

    Open questions at the time
    • Structural basis of inter-module assembly not resolved
    • Efficiency relative to native receptor unclear
  10. 2013 High

    The residues controlling Zn2+ allosteric potentiation were unknown; W170S reduced Zn2+ potentiation and enhanced Zn2+ inhibition, mapping the potentiation site distinct from H107 inhibition.

    Evidence Recombinant expression with temporal Zn2+ electrophysiology and H107N background dissection, confirmed in neurons

    PMID:24198360

    Open questions at the time
    • Single lab
    • Endogenous Zn2+ regulation in vivo not addressed
  11. 2019 High

    Whether alpha1 is uniquely required among alpha subunits was untested; individual CRISPR knockouts showed only glra1 loss causes motor dysfunction, establishing non-redundancy.

    Evidence CRISPR/Cas9 knockout of each alpha subunit with behavioral analysis in zebrafish

    PMID:31048868

    Open questions at the time
    • Does not address subunit roles in other circuits or species
    • Molecular basis of non-redundancy not detailed
  12. 2020 Medium

    Whether partial GLRA1 dysfunction affects circuits beyond startle was unclear; spasmodic A52S mice showed altered fear-related behaviors alongside enhanced startle.

    Evidence Behavioral startle and fear-context analysis in Glra1 spasmodic mice

    PMID:32848605

    Open questions at the time
    • Behavioral correlation does not establish circuit mechanism
    • Single study
  13. 2025 High

    A non-neuronal role for GLRA1 was unknown; it was shown to bind calmodulin in pancreatic beta cells to maintain ER calcium homeostasis and support insulin secretion, defining a glycine-GLRA1-calmodulin-ER calcium axis.

    Evidence Co-IP, beta-cell-specific conditional knockout, ER calcium imaging, ER stress and insulin secretion assays

    PMID:42037784

    Open questions at the time
    • Single lab
    • Whether interaction depends on channel activity not resolved
    • Mechanistic link between calmodulin binding and ER calcium undefined

Open questions

Synthesis pass · forward-looking unresolved questions
  • How alpha1 mechanistically stabilizes gephyrin and how its calmodulin-dependent ER calcium role in beta cells relates to its channel function remain unresolved.
  • No structural model of the receptor-gephyrin interface from the corpus
  • Channel-dependence of beta-cell calmodulin axis unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005215 transporter activity 3
Localization
GO:0005886 plasma membrane 2 GO:0005783 endoplasmic reticulum 1
Pathway
R-HSA-112316 Neuronal System 2 R-HSA-162582 Signal Transduction 1
Partners
CALM1GLRBGPHN
Complex memberships
Glycine receptor (alpha1/beta pentamer)

Evidence

Reading pass · 13 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1992 The GLRA1 (STHE) gene was mapped to chromosome 5q33-q35 by linkage analysis in a large hyperekplexia pedigree, establishing its chromosomal locus and candidacy as the startle disease gene. Systematic linkage analysis with polymorphic genetic markers Annals of neurology High 1355335
1994 GLRA1 encodes the alpha1 subunit of the adult glycine receptor, which assembles into a pentameric complex (3 alpha1 : 2 beta) forming a glycine-gated chloride channel; loss-of-function frameshift mutation in mouse Glra1 (oscillator) causes 90% reduction in glycine-displaceable strychnine binding, confirming alpha1 is required for functional receptor activity and that no other alpha subunit compensates. Radioligand binding ([3H]strychnine), genetic mapping, allelism testing with spasmodic mutant Human molecular genetics High 7874121
1997 Complete loss of GLRA1 alpha1 polypeptide in oscillator (Glra1 spd-ot) homozygous mice also causes a dramatic reduction in the postsynaptic anchoring protein gephyrin, demonstrating that alpha1 is required for normal gephyrin localization/stability at glycinergic synapses. Western blot with subunit-specific antibodies, [3H]strychnine binding, immunoanalysis Neuroscience High 9145798
1999 The hyperekplexia missense mutation P250T in the cytoplasmic M1-M2 loop of GLRA1 causes strong reduction of maximum whole-cell chloride currents and altered (prolonged) desensitization recovery, with only ~5-fold increase in glycine Ki, defining the M1-M2 intracellular loop as a determinant of glycine receptor channel gating. Recombinant expression in HEK293 cells, patch-clamp electrophysiology, topological analysis The Journal of neuroscience High 9920650
2002 The recessive hyperekplexia mutation S231R in transmembrane region TM1 of GLRA1 introduces a positive charge that disrupts glycine receptor biogenesis and reduces surface membrane integration without abolishing expression, identifying TM1 as a determinant of cellular receptor trafficking. Biochemical analysis, patch-clamp electrophysiology, confocal microscopy, MALDI-TOF genotyping European journal of human genetics High 11973623
2007 The hyperekplexia dominant missense mutation S267N in GLRA1 affects agonist responses and abolishes ethanol modulation of the glycine receptor, identifying S267 in TM2 as part of the ethanol/anesthetic modulatory site. Recombinant expression, electrophysiology, pharmacological modulation assays European journal of human genetics Medium 18043720
2009 The C-terminal domain of GLRA1 (including TM3-TM4 and the intervening loop) functions as an autonomous module: coexpression of a tail construct encoding the deleted C-terminal sequence rescued glycine-gated ion channel activity in oscillator truncation mutants, demonstrating modular subunit architecture of the Cys-loop receptor. Recombinant coexpression, electrophysiology, viral infection of oscillator spinal cord neurons, immunostaining The Journal of neuroscience High 19244519
2010 Systematic functional analysis of 13 GLRA1 hyperekplexia mutations showed that recessive mutations primarily cause subcellular localization/trafficking defects (reduced surface expression), while mutations without trafficking defects alter glycine sensitivity, establishing two major pathophysiological mechanisms; additionally, mutation I244N produces a constitutive leak conductance, identifying tonic channel opening as a novel mechanism. High-content imaging of subcellular localization, patch-clamp electrophysiology in HEK293 cells expressing homomeric alpha1 or heteromeric alpha1beta GlyRs The Journal of neuroscience High 20631190
2013 The hyperekplexia missense mutation W170S in the extracellular domain of GLRA1 reduces Zn2+-mediated potentiation and enhances Zn2+ inhibition of glycine receptors without altering glycine, taurine, or β-alanine potency, identifying W170 as a critical residue for the Zn2+ potentiation site distinct from the Zn2+ inhibition site (H107). Recombinant expression of alpha1 and alpha1beta GlyRs in heterologous cells, whole-cell electrophysiology with temporal Zn2+ application, overexpression in cultured rat neurons; H107N background mutation used for site dissection The Journal of neuroscience High 24198360
2019 CRISPR/Cas9 knockout of glra1 in zebrafish causes strong motor dysfunction and premature death, while knockout of glra2, glra3, glra4a, or glra4b produces no obvious motor phenotype, establishing that glra1 is specifically and non-redundantly required for inhibitory neurotransmission controlling locomotion. CRISPR/Cas9-targeted mutagenesis, individual knockout of each alpha subunit, behavioral motor analysis PloS one High 31048868
2025 GLRA1 forms a physical interaction with calmodulin in pancreatic beta cells to sustain endoplasmic reticulum calcium homeostasis; beta-cell-specific deletion of Glra1 disrupts ER calcium dynamics, amplifies ER stress, and impairs insulin gene expression and secretion, establishing a glycine-GLRA1-calmodulin-ER calcium signaling axis in beta-cell function. Co-immunoprecipitation (GLRA1-calmodulin interaction), beta-cell-specific conditional knockout, ER calcium imaging, ER stress assays, insulin secretion assays, overexpression of Shmt2 Life metabolism High 42037784
1996 Homozygous deletion of exons 1-6 of GLRA1 (complete null allele) in a human patient causes non-lethal hyperekplexia with preserved proprio- and exteroceptive inhibition, demonstrating that complete loss of GLRA1 is survivable in humans (unlike in mice) and that some glycinergic functions are compensated by other mechanisms. Genomic deletion analysis, clinical phenotyping of consanguineous family American journal of human genetics Medium 8651283
2020 Spasmodic mice carrying a Glra1 point mutation (A52S) display enhanced acoustic startle responses and significant changes in fear-related behaviors (freezing, rearing, time on back) even in a neutral context, demonstrating that partial loss of GLRA1 function affects both startle magnitude and fear-related behavioral circuits. Behavioral analysis (startle paradigm, fear conditioning context) in Glra1 spasmodic and Glrb spastic mouse mutants Frontiers in molecular neuroscience Medium 32848605

Source papers

Stage 0 corpus · 44 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1985 Determination of plasma protein S--the protein cofactor of activated protein C. Thrombosis and haemostasis 180 3161206
2010 Pathophysiological mechanisms of dominant and recessive GLRA1 mutations in hyperekplexia. The Journal of neuroscience : the official journal of the Society for Neuroscience 113 20631190
1992 Startle disease, or hyperekplexia: response to clonazepam and assignment of the gene (STHE) to chromosome 5q by linkage analysis. Annals of neurology 107 1355335
1994 A frameshift mutation in the mouse alpha 1 glycine receptor gene (Glra1) results in progressive neurological symptoms and juvenile death. Human molecular genetics 103 7874121
1999 Novel GLRA1 missense mutation (P250T) in dominant hyperekplexia defines an intracellular determinant of glycine receptor channel gating. The Journal of neuroscience : the official journal of the Society for Neuroscience 85 9920650
1996 A GLRA1 null mutation in recessive hyperekplexia challenges the functional role of glycine receptors. American journal of human genetics 69 8651283
1997 The frameshift mutation oscillator (Glra1(spd-ot)) produces a complete loss of glycine receptor alpha1-polypeptide in mouse central nervous system. Neuroscience 68 9145798
1996 Analysis of GLRA1 in hereditary and sporadic hyperekplexia: a novel mutation in a family cosegregating for hyperekplexia and spastic paraparesis. Journal of medical genetics 64 8733061
1999 Hyperekplexia phenotype due to compound heterozygosity for GLRA1 gene mutations. Annals of neurology 47 10514101
2002 A novel recessive hyperekplexia allele GLRA1 (S231R): genotyping by MALDI-TOF mass spectrometry and functional characterisation as a determinant of cellular glycine receptor trafficking. European journal of human genetics : EJHG 35 11973623
1997 Hyperekplexia-like syndromes without mutations in the GLRA1 gene. Clinical neurology and neurosurgery 29 9350397
2009 Functional complementation of Glra1(spd-ot), a glycine receptor subunit mutant, by independently expressed C-terminal domains. The Journal of neuroscience : the official journal of the Society for Neuroscience 24 19244519
2012 Novel mutation of GLRA1 in Omani families with hyperekplexia and mild mental retardation. Pediatric neurology 19 22264702
2013 The GLRA1 missense mutation W170S associates lack of Zn2+ potentiation with human hyperekplexia. The Journal of neuroscience : the official journal of the Society for Neuroscience 17 24198360
2008 A novel GLRA1 mutation associated with an atypical hyperekplexia phenotype. Journal of child neurology 15 19073849
2007 The novel hyperekplexia allele GLRA1(S267N) affects the ethanol site of the glycine receptor. European journal of human genetics : EJHG 15 18043720
2005 Recessive hyperekplexia due to a new mutation (R100H) in the GLRA1 gene. Movement disorders : official journal of the Movement Disorder Society 13 16078201
2020 Anxiety and Startle Phenotypes in Glrb Spastic and Glra1 Spasmodic Mouse Mutants. Frontiers in molecular neuroscience 12 32848605
2007 A novel GLRA1 mutation in a recessive hyperekplexia pedigree. Movement disorders : official journal of the Movement Disorder Society 12 17534957
2006 De novo exon duplication in a new allele of mouse Glra1 (spasmodic). Genetics 12 17028313
2019 Individual knock out of glycine receptor alpha subunits identifies a specific requirement of glra1 for motor function in zebrafish. PloS one 11 31048868
2014 Ethnicity can predict GLRA1 genotypes in hyperekplexia. Journal of neurology, neurosurgery, and psychiatry 11 24970905
2004 Hereditary hyperekplexia caused by novel mutations of GLRA1 in Turkish families. Molecular diagnosis : a journal devoted to the understanding of human disease through the clinical application of molecular biology 11 15771552
2014 Identification of a novel missense GLRA1 gene mutation in hyperekplexia: a case report. Journal of medical case reports 10 24969041
2006 Hyperekplexia in Kurdish families: a possible GLRA1 founder mutation. Neurology 10 16832093
2022 Hereditary Hyperekplexia: A New Family and a Systematic Review of GLRA1 Gene-Related Phenotypes. Pediatric neurology 9 35636282
2003 Hyperekplexia (startle disease): a novel mutation (S270T) in the M2 domain of the GLRA1 gene and a molecular review of the disorder. Molecular diagnosis : a journal devoted to the understanding of human disease through the clinical application of molecular biology 9 14580232
2020 Excessive Startle with Novel GLRA1 Mutations in 4 Chinese Patients and a Literature Review of GLRA1-Related Hyperekplexia. Journal of clinical neurology (Seoul, Korea) 8 32319239
2012 Hyperekplexia: a Chinese adolescent with 2 novel mutations of the GLRA1 gene. Journal of child neurology 8 23143726
2017 Dimensional Traits of Schizotypy Associated With Glycine Receptor GLRA1 Polymorphism: An Exploratory Candidate-Gene Association Study. Journal of personality disorders 7 28758885
2023 A loss-of-function variant in canine GLRA1 associates with a neurological disorder resembling human hyperekplexia. Human genetics 6 37222814
2018 Weird Laughing in Hyperekplexia: A new phenotype associated with a novel mutation in the GLRA1 gene? Seizure 6 29602144
2017 A novel compound mutation in GLRA1 cause hyperekplexia in a Chinese boy- a case report and review of the literature. BMC medical genetics 5 28985719
2018 A novel nonsense autosomal dominant mutation in the GLRA1 gene causing hyperekplexia. Journal of neural transmission (Vienna, Austria : 1996) 4 30182260
1991 [Increasing the sensitivity of in vitro transformed hamster embryo cells (STHE strain) to cytolysis by resident and activated macrophages]. Biulleten' eksperimental'noi biologii i meditsiny 3 2054477
2022 Four Turkish families with hyperekplexia: A missense mutation and the exon 1-7 deletion in the GLRA1 gene. Parkinsonism & related disorders 2 36434917
2020 C.292G>A, a novel glycine receptor alpha 1 subunit gene (GLRA1) mutation found in a Chinese patient with hyperekplexia: A case report. Medicine 2 32332682
2014 Neonatal hyperekplexia with homozygous p.R392H mutation in GLRA1. Epileptic disorders : international epilepsy journal with videotape 2 25036534
2003 Magnetic resonance spectroscopy of cerebral cortex is normal in hereditary hyperekplexia due to mutations in the GLRA1 gene. Movement disorders : official journal of the Movement Disorder Society 2 14673895
2025 A Novel Variant in GLRA1 Associated With Emotional Stimulus-Sensitive Hemichoreic Movements. American journal of medical genetics. Part A 1 41194486
1991 [In vitro selection of cell variants resistant to macrophage and hydrogen peroxide cytotoxic activity in spontaneous transformed cells of the STHE strain]. Biulleten' eksperimental'noi biologii i meditsiny 1 1786389
1991 [The tumorigenicity and metastasis of low-malignancy STHE-strain cells undergoing in vitro selection with peritoneal exudate cells]. Biulleten' eksperimental'noi biologii i meditsiny 1 1810496
2026 A case of childhood hyperekplexia due to a novel nonsense variant in the GLRA1 gene. Medicine 0 41578547
2025 Glycine-GLRA1-calmodulin signaling regulates endoplasmic reticulum calcium to sustain insulin secretion and β-cell function. Life metabolism 0 42037784

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