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glycine receptor α1 subunit

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Target not currently curated in GtoImmuPdb

Target id: 423

Nomenclature: glycine receptor α1 subunit

Family: Glycine receptors

Contents:

Gene and Protein Information Click here for help
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human 4 457 5q33.1 GLRA1 glycine receptor alpha 1 9
Mouse 4 457 11 33.12 cM Glra1 glycine receptor, alpha 1 subunit 17
Rat 4 457 10q22 Glra1 glycine receptor, alpha 1 26
Previous and Unofficial Names Click here for help
GLYRA1 | glycine receptor strychnine-binding subunit | STHE | glycine receptor
Database Links Click here for help
Alphafold P23415 (Hs), Q64018 (Mm), P07727 (Rn)
CATH/Gene3D 2.70.170.10
ChEMBL Target CHEMBL5845 (Hs), CHEMBL4295860 (Mm), CHEMBL3246 (Rn)
DrugBank Target P23415 (Hs), P23415 (Hs)
Ensembl Gene ENSG00000145888 (Hs), ENSMUSG00000000263 (Mm), ENSRNOG00000013588 (Rn)
Entrez Gene 2741 (Hs), 14654 (Mm), 25674 (Rn)
Human Protein Atlas ENSG00000145888 (Hs)
KEGG Gene hsa:2741 (Hs), mmu:14654 (Mm), rno:25674 (Rn)
OMIM 138491 (Hs)
Orphanet ORPHA122179 (Hs)
Pharos P23415 (Hs)
RefSeq Nucleotide NM_000171 (Hs), NM_020492 (Mm), NM_013133 (Rn)
RefSeq Protein NP_000162 (Hs), NP_065238 (Mm), NP_037265 (Rn)
UniProtKB P23415 (Hs), Q64018 (Mm), P07727 (Rn)
Wikipedia GLRA1 (Hs)
Functional Characteristics Click here for help
γ = 86 pS (main state); (+ β = 44 pS)
Natural/Endogenous Ligands Click here for help
Cu2+
glycine
H+
Zn2+
Selective agonists (potency order) (Human)
glycine > β-alanine > taurine

Download all structure-activity data for this target as a CSV file go icon to follow link

Antagonists
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
pregnenolone sulphate Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Antagonist 5.7 pKi
⤷ pKi 5.7 (Ki 1.9x10-6 M)
tropisetron Small molecule or natural product Approved drug Click here for species-specific activity table Ligand has a PDB structure Hs Antagonist 4.1 pKi
⤷ pKi 4.1 (Ki 8.4x10-5 M)
ginkgolide X Small molecule or natural product Click here for species-specific activity table Hs Antagonist 6.1 pIC50
⤷ pIC50 6.1 (IC50 7.6x10-7 M)
nifedipine Small molecule or natural product Approved drug Click here for species-specific activity table Ligand has a PDB structure Hs Antagonist 5.5 pIC50
⤷ pIC50 5.5 (IC50 3.3x10-6 M)
bilobalide Small molecule or natural product Click here for species-specific activity table Hs Antagonist 4.7 pIC50
⤷ pIC50 4.7 (IC50 2x10-5 M)
colchicine Small molecule or natural product Approved drug Click here for species-specific activity table Ligand has a PDB structure Immunopharmacology Ligand Hs Antagonist 3.5 pIC50
⤷ pIC50 3.5 (IC50 3.24x10-4 M)
strychnine Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Antagonist - -
⤷
onternabez Small molecule or natural product Click here for species-specific activity table Hs Antagonist - -
⤷ weak inhibition
[3H]strychnine Small molecule or natural product Click here for species-specific activity table Ligand is labelled Ligand is radioactive Ligand has a PDB structure Hs Antagonist - -
⤷
PMBA Small molecule or natural product Click here for species-specific activity table Hs Antagonist - -
⤷
Channel Blockers
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Use-dependent Value Parameter Concentration range (M) Voltage-dependent (mV) Reference
cyanotriphenylborate Small molecule or natural product Click here for species-specific activity table Hs - no 5.9 pIC50 - no 20
⤷ pIC50 5.9 (IC50 1.3x10-6 M) [20]
Not voltage dependent
ginkgolide B Small molecule or natural product Click here for species-specific activity table Hs - no 5.1 – 6.2 pIC50 - no
⤷ pIC50 5.1 – 6.2 (IC50 8x10-6 – 6x10-7 M)
Not voltage dependent
picrotoxinin Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs - no 5.3 pIC50 - no
⤷ pIC50 5.3 (IC50 5.1x10-6 M)
Not voltage dependent
picrotin Small molecule or natural product Click here for species-specific activity table Hs - no 5.3 pIC50 - no
⤷ pIC50 5.3 (IC50 5.2x10-6 M)
Not voltage dependent
picrotoxin Small molecule or natural product Click here for species-specific activity table Hs - no 5.2 pIC50 - no
⤷ pIC50 5.2 (IC50 6.3x10-6 M)
Not voltage dependent
Allosteric Modulators
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Concentration range (M) Voltage-dependent (mV) Reference
Zn2+ Click here for species-specific activity table Ligand is endogenous in the given species Hs Potentiation 7.4 pEC50 - no
⤷ pEC50 7.4 (EC50 3.7x10-8 M) endogenous; not affected by β subunit co-expression
Not voltage dependent
anandamide Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Potentiation 7.4 pEC50 - no
⤷ pEC50 7.4 (EC50 3.8x10-8 M)
Not voltage dependent
HU-210 Small molecule or natural product Click here for species-specific activity table Hs Potentiation 6.6 pEC50 - no
⤷ pEC50 6.6 (EC50 2.7x10-7 M)
Not voltage dependent
Δ9-tetrahydrocannabinol Small molecule or natural product Approved drug Click here for species-specific activity table Ligand has a PDB structure Hs Potentiation ~5.5 pEC50 - no
⤷ pEC50 ~5.5 (EC50 ~3x10-6 M) ~1500% potentiation
Not voltage dependent
Cu2+ Click here for species-specific activity table Ligand is endogenous in the given species Hs Inhibition 4.8 – 5.4 pIC50 - no
⤷ pIC50 4.8 – 5.4 (IC50 1.5x10-5 – 4x10-6 M) endogenous; not affected by β subunit co-expression
Not voltage dependent
Zn2+ Click here for species-specific activity table Ligand is endogenous in the given species Hs Inhibition 4.8 pIC50 - no
⤷ pIC50 4.8 (IC50 1.5x10-5 M) endogenous
Not voltage dependent
Extracellular H+ Click here for species-specific activity table Ligand is endogenous in the given species Hs Inhibition - - - no
⤷ endogenous
Not voltage dependent
Tissue Distribution Click here for help
Spinal cord, trigeminal nuclei, superior olive nucleus, nuclei of lateral lemniscus, vestibular nuclei, cuneate nucleus, gracile nucleus, hypoglossal nucleus, dorsal motor nucleus of vagus, superior colliculus
Species:  Human
Technique:  Strychnine Autoradiography (does not distinguish among α GlyR subtypes)
References:  19
Retina (subset of ganglion cells in inner nuclear layer)
Species:  Mouse
Technique:  Immunohistochemistry
References:  10
Sperm
Species:  Mouse
Technique:  Immunohistochemistry (does not distinguish among α GlyR subtypes)
References:  24
Spinal cord, superior and inferior colliculi, hypothalamus, parafascicular nucleus, brain stem nuclei.
Species:  Rat
Technique:  In situ hybridisation
References:  16
Cranial nuclei, sensory nuclei such as the spinal trigeminal nucleus, principal trigeminal nucleus, gracile and cuneate nuclei, dorsal and ventral cochlear nuclei, superior olivary nucleus, medial and lateral trapezoid nuclei, lateral lemniscus and vestibular nuclei, red nucleus, parabrachial area, cerebellar nuclei, dorsal tegmental nucleus, reticular formation, parafascicular nucleus.
Species:  Rat
Technique:  In situ hybridisation
References:  23
Spinal cord, trigeminal nuclei, superior olive nucleus, nuclei of lateral lemniscus, vestibular nuclei, cuneate nucleus, gracile nucleus, hypoglossal nucleus, dorsal motor nucleus of vagus, superior colliculus.
Species:  Rat
Technique:  Strychnine Autoradiography (does not distinguish among α GlyR subtypes)
References:  28
Kupffer cells, neutrophils and macrophages
Species:  Rat
Technique:  RT-PCR
References:  7
Neural stem progenitor cells
Species:  Rat
Technique:  RT-PCR
References:  18
Retina (subset of ganglion cells in inner nuclear layer)
Species:  Rat
Technique:  Immunohistochemistry
References:  11
Retina (bipolar cells, subset of ganglion cells in inner nuclear layer)
Species:  Rat
Technique:  In situ hybridisation and immunohistochemistry
References:  8,22
Cochlear nuclei, trigeminal motor nucleus, parabrachial area, lateral reticular nucleus, dorsal nucleus of the lateral lemniscus, cerebellar nuclei, trigeminal spinal nucleus, anterior horn and reticular formation, cerebellum.
Species:  Rat
Technique:  Immunocytochemistry (does not distinguish among α GlyR subtypes)
References:  1
Spinal cord, olfactory bulb, cerebellum, hippocampus.
Species:  Rat
Technique:  Immunocytochemistry (does not distinguish among α GlyR subtypes)
References:  27
Physiological Consequences of Altering Gene Expression Click here for help
Overexpression of the D80A mutant α1 GlyR in mouse eliminates zinc potentiation of synaptic α1 GlyRs. Knock-in mice developed both motor and sensory deficits typical of impaired glycinergic transmission: inducible tremor, delayed righting reflex, abnormal gait, and an enhanced acoustic startle response.
Species:  Mouse
Tissue:  in vivo
Technique:  Homologous recombination of D80A mutant α1 GlyR at the Glra1 gene locus.
References:  12
Overexpression of the S267Q mutant α1 GlyR in mouse reulted in a decrease in alcohol sensitivity, limb clenching and an enhanced acoustic startle response. The mutation is thought to ablate the putative alcohol binding site.
Species:  Mouse
Tissue:  in vivo
Technique:  Homologous recombination of S267Q mutant α1 GlyR at the Glra1 gene locus.
References:  4-6
Clinically-Relevant Mutations and Pathophysiology Click here for help
Disease:  Hyperekplexia, hereditary 1; HKPX1
Synonyms: Hereditary hyperekplexia [Orphanet: ORPHA3197]
OMIM: 149400
Orphanet: ORPHA3197
Role:  Around 20 α1 GlyR mutations have been identified to date in ~70 human hyperekplexia pedigrees. All known mutations reduce the magnitude of α1 GlyR-mediated currents, with some completely eliminating α1GlyR expression or function.
Drugs:  Clonazepam
Comments:  All mutations produce similar symptoms although the severity may vary. The main symptom in adults is an exaggerated and generalised startle reflex to unexpected and sometimes trivial stimuli. This is often accompanied by temporary but complete muscular rigidity, often resulting in unprotected falls. Neonates also usually display a severe muscular rigidity (hypertonia) that subsides throughout the first year of life.
References:  2
Biologically Significant Variants Click here for help
Type:  Missense mutation
Species:  Mouse
Description:  In the spasmodic mouse, a mutation in α1 GlyR results in a 6 fold decrease in glycine sensitivity. Symptoms are similar to human hyperekplexia.
Amino acid change:  A52S
References:  21,25
Type:  Frameshift mutation
Species:  Mouse
Description:  The Cincinatti mouse has a duplication of exon 5 results in a frameshift and premature protein truncation. This leads to a reduction of magnitude of α1-mediated currents The symptoms are similar to human hyperekplexia.
Amino acid change:  Duplication of exon 5
References:  13
Type:  Deletion
Species:  Mouse
Description:  Oscillator mice have a deletion of 7 nucleotides in the Glra1 gene. Homozygous oscillator mice appear normal until the second week of life, whereupon they develop progressively worsening muscular rigidity and tremor, spastic gait, exaggerated startle responses and die within 10 days.
Amino acid change:  A premature stop codon in the α1 GlyR large intracellular domain.
References:  3,14
General Comments
The rat glycine receptor α1 subunit exists as two alternatively spliced isoforms [15], provisionally termed α1 and α1INS. The latter contains an eight amino acid insertion within the large intracellular region between TM3 and TM4 [17].

References

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1. Araki T, Yamano M, Murakami T, Wanaka A, Betz H, Tohyama M. (1988) Localization of glycine receptors in the rat central nervous system: an immunocytochemical analysis using monoclonal antibody. Neuroscience, 25 (2): 613-24. [PMID:2840602]

2. Bakker MJ, van Dijk JG, van den Maagdenberg AM, Tijssen MA. (2006) Startle syndromes. Lancet Neurol, 5 (6): 513-24. [PMID:16713923]

3. Buckwalter MS, Cook SA, Davisson MT, White WF, Camper SA. (1994) A frameshift mutation in the mouse alpha 1 glycine receptor gene (Glra1) results in progressive neurological symptoms and juvenile death. Hum Mol Genet, 3 (11): 2025-30. [PMID:7874121]

4. Findlay GS, Harris RA, Blednov YA. (2005) Male transgenic glycine receptor alpha1 (S267Q) mutant mice display a hyperekplexia-like increase in acoustic startle responses. Pharmacol Biochem Behav, 82 (1): 215-22. [PMID:16168470]

5. Findlay GS, Phelan R, Roberts MT, Homanics GE, Bergeson SE, Lopreato GF, Mihic SJ, Blednov YA, Harris RA. (2003) Glycine receptor knock-in mice and hyperekplexia-like phenotypes: comparisons with the null mutant. J Neurosci, 23 (22): 8051-9. [PMID:12954867]

6. Findlay GS, Wick MJ, Mascia MP, Wallace D, Miller GW, Harris RA, Blednov YA. (2002) Transgenic expression of a mutant glycine receptor decreases alcohol sensitivity of mice. J Pharmacol Exp Ther, 300 (2): 526-34. [PMID:11805213]

7. Froh M, Thurman RG, Wheeler MD. (2002) Molecular evidence for a glycine-gated chloride channel in macrophages and leukocytes. Am J Physiol Gastrointest Liver Physiol, 283 (4): G856-63. [PMID:12223345]

8. Greferath U, Brandstätter JH, Wässle H, Kirsch J, Kuhse J, Grünert U. (1994) Differential expression of glycine receptor subunits in the retina of the rat: a study using immunohistochemistry and in situ hybridization. Vis Neurosci, 11 (4): 721-9. [PMID:7918222]

9. Grenningloh G, Schmieden V, Schofield PR, Seeburg PH, Siddique T, Mohandas TK, Becker CM, Betz H. (1990) Alpha subunit variants of the human glycine receptor: primary structures, functional expression and chromosomal localization of the corresponding genes. EMBO J, 9 (3): 771-6. [PMID:2155780]

10. Grünert U, Ghosh KK. (1999) Midget and parasol ganglion cells of the primate retina express the alpha1 subunit of the glycine receptor. Vis Neurosci, 16 (5): 957-66. [PMID:10580731]

11. Grünert U, Wässle H. (1993) Immunocytochemical localization of glycine receptors in the mammalian retina. J Comp Neurol, 335 (4): 523-37. [PMID:8227534]

12. Hirzel K, Müller U, Latal AT, Hülsmann S, Grudzinska J, Seeliger MW, Betz H, Laube B. (2006) Hyperekplexia phenotype of glycine receptor alpha1 subunit mutant mice identifies Zn(2+) as an essential endogenous modulator of glycinergic neurotransmission. Neuron, 52 (4): 679-90. [PMID:17114051]

13. Holland KD, Fleming MT, Cheek S, Moran JL, Beier DR, Meisler MH. (2006) De novo exon duplication in a new allele of mouse Glra1 (spasmodic). Genetics, 174 (4): 2245-7. [PMID:17028313]

14. Kling C, Koch M, Saul B, Becker CM. (1997) The frameshift mutation oscillator (Glra1(spd-ot)) produces a complete loss of glycine receptor alpha1-polypeptide in mouse central nervous system. Neuroscience, 78 (2): 411-7. [PMID:9145798]

15. Malosio ML, Grenningloh G, Kuhse J, Schmieden V, Schmitt B, Prior P, Betz H. (1991) Alternative splicing generates two variants of the alpha 1 subunit of the inhibitory glycine receptor. J Biol Chem, 266 (4): 2048-53. [PMID:1703526]

16. Malosio ML, Marquèze-Pouey B, Kuhse J, Betz H. (1991) Widespread expression of glycine receptor subunit mRNAs in the adult and developing rat brain. EMBO J, 10 (9): 2401-9. [PMID:1651228]

17. Matzenbach B, Maulet Y, Sefton L, Courtier B, Avner P, Guénet JL, Betz H. (1994) Structural analysis of mouse glycine receptor alpha subunit genes. Identification and chromosomal localization of a novel variant. J Biol Chem, 269 (4): 2607-12. [PMID:7507926]

18. Nguyen L, Malgrange B, Belachew S, Rogister B, Rocher V, Moonen G, Rigo JM. (2002) Functional glycine receptors are expressed by postnatal nestin-positive neural stem/progenitor cells. Eur J Neurosci, 15 (8): 1299-305. [PMID:11994124]

19. Probst A, Cortés R, Palacios JM. (1986) The distribution of glycine receptors in the human brain. A light microscopic autoradiographic study using [3H]strychnine. Neuroscience, 17 (1): 11-35. [PMID:3008022]

20. Rundström N, Schmieden V, Betz H, Bormann J, Langosch D. (1994) Cyanotriphenylborate: subtype-specific blocker of glycine receptor chloride channels. Proc Natl Acad Sci USA, 91 (19): 8950-4. [PMID:8090751]

21. Ryan SG, Buckwalter MS, Lynch JW, Handford CA, Segura L, Shiang R, Wasmuth JJ, Camper SA, Schofield P, O'Connell P. (1994) A missense mutation in the gene encoding the alpha 1 subunit of the inhibitory glycine receptor in the spasmodic mouse. Nat Genet, 7 (2): 131-5. [PMID:7920629]

22. Sassoè-Pognetto M, Wässle H, Grünert U. (1994) Glycinergic synapses in the rod pathway of the rat retina: cone bipolar cells express the alpha 1 subunit of the glycine receptor. J Neurosci, 14 (8): 5131-46. [PMID:8046473]

23. Sato K, Zhang JH, Saika T, Sato M, Tada K, Tohyama M. (1991) Localization of glycine receptor alpha 1 subunit mRNA-containing neurons in the rat brain: an analysis using in situ hybridization histochemistry. Neuroscience, 43 (2-3): 381-95. [PMID:1656320]

24. Sato Y, Son JH, Meizel S. (2000) The mouse sperm glycine receptor/chloride channel: cellular localization and involvement in the acrosome reaction initiated by glycine. J Androl, 21 (1): 99-106. [PMID:10670525]

25. Saul B, Schmieden V, Kling C, Mülhardt C, Gass P, Kuhse J, Becker CM. (1994) Point mutation of glycine receptor alpha 1 subunit in the spasmodic mouse affects agonist responses. FEBS Lett, 350 (1): 71-6. [PMID:8062927]

26. Sontheimer H, Becker CM, Pritchett DB, Schofield PR, Grenningloh G, Kettenmann H, Betz H, Seeburg PH. (1989) Functional chloride channels by mammalian cell expression of rat glycine receptor subunit. Neuron, 2 (5): 1491-7. [PMID:2483325]

27. van den Pol AN, Gorcs T. (1988) Glycine and glycine receptor immunoreactivity in brain and spinal cord. J Neurosci, 8 (2): 472-92. [PMID:2892900]

28. Zarbin MA, Wamsley JK, Kuhar MJ. (1981) Glycine receptor: light microscopic autoradiographic localization with [3H]strychnine. J Neurosci, 1 (5): 532-47. [PMID:6286895]

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