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α1

Family: Glycine receptors

Contents:
Gene and Protein Information
Previous and Unofficial Names
Database Links
Tissue Distribution
Physiological Consequences of Altering Gene Expression
Clinically-Relevant Mutations and Pathophysiology
General Comments
References
Gene and Protein Information
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human 4 449 5q32 GLRA1 glycine receptor, alpha 1 9
Mouse 4 457 11 B1.3 Glra1 glycine receptor, alpha 1 subunit 17
Rat 4 457 10q22 Glra1 glycine receptor, alpha 1 25
Previous and Unofficial Names
STHE
glycine receptor, alpha 1 (startle disease/hyperekplexia)
startle disease/hyperekplexia
stiff person syndrome
GLYRA1
glycine receptor 48 kDa subunit
glycine receptor strychnine-binding subunit
glycine receptor subunit alpha-1
glycine receptor, alpha 1
glycine receptor, alpha 1 subunit
ot
oscillator
nmf11
B230397M16Rik
spd
Database Links
ChEMBL Target 102688 (Hs), 12235 (Rn)
DrugBank Target 482 (Hs)
Ensembl ENSG00000145888 (Hs), ENSMUSG00000000263 (Mm), ENSRNOG00000013588 (Rn)
Entrez Gene 2741 (Hs), 14654 (Mm), 25674 (Rn)
GeneCards GLRA1 (Hs)
GenitoUrinary Development Molecular Anatomy Project Glra1 (Mm)
HomoloGene 20083 (Hs)
Human Protein Reference Database 00719 (Hs)
InterPro P23415 (Hs), Q64018 (Mm), P07727 (Rn)
KEGG Gene hsa:2741 (Hs), mmu:14654 (Mm), rno:25674 (Rn)
OMIM 138491 (Hs)
Orphanet Gene ORPHA122179 (Hs)
PharmGKB Gene PA28727 (Hs)
PhosphoSitePlus P23415 (Hs), Q64018 (Mm)
Protein Ontology (PRO) PRO:000008042 (Hs)
RefSeq Nucleotide NM_000171 (Hs), NM_020492 (Mm), NM_013133 (Rn)
RefSeq Protein NP_000162 (Hs), NP_065238 (Mm), NP_037265 (Rn)
TreeFam ENSG00000145888 (Hs), ENSMUSG00000000263 (Mm), ENSRNOG00000013588 (Rn)
UniGene Hs. 121490 (Hs)
UniProt P23415 (Hs), Q64018 (Mm), P07727 (Rn)
Wikipedia α1
Glycine receptors
Search for 3D structures on the PDB
Search by keyword: Glycine receptors α1 Search by accession number: Q64018, P07727, P23415
Natural/Endogenous Ligand(s)
glycine
Selective agonists (potency order) (Human)
glycine > β-alanine > taurine
Tissue Distribution
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:  23
Spinal cord, olfactory bulb, cerebellum, hippocampus.
Species:  Rat
Technique:  Immunocytochemistry (does not distinguish among α GlyR subtypes)
References:  26
Spinal cord, superior and inferior colliculi, hypothalamus, parafascicular nucleus, brain stem nuclei.
Species:  Rat
Technique:  In situ hybridisation
References:  16
Neural stem progenitor cells
Species:  Rat
Technique:  RT-PCR
References:  18
Retina (bipolar cells, subset of ganglion cells in inner nuclear layer)
Species:  Rat
Technique:  In situ hybridisation and immunohistochemistry
References:  8,21
Kupffer cells, neutrophils and macrophages
Species:  Rat
Technique:  RT-PCR
References:  7
Retina (subset of ganglion cells in inner nuclear layer)
Species:  Rat
Technique:  Immunohistochemistry
References:  11
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:  22
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:  27
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
Physiological Consequences of Altering Gene Expression
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
Disease:  Spasmodic mouse
Role:  A mutation in α1 GlyR results in a 6 fold decrease in glycine sensitivity.
Comments:  Symptoms are similar to human hyperekplexia.
References:  20,24
Click column headers to sort
Type Species Molecular location Description Reference
None Mouse A52S 20,24
Disease:  Oscillator mouse
Role:  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.
Comments:  It is a deletion of 7 nucleotides.
References:  3,14
Click column headers to sort
Type Species Molecular location Description Reference
Deletion Mouse A premature stop codon in the α1 GlyR large intracellular domain. 3,14
Disease:  Cincinatti mouse
Role:  Reduction of magnitude of α1-mediated currents
Comments:  Duplication of exon 5 results in a frameshift and premature protein truncation. The symptoms are similar to human hyperekplexia.
References:  13
Click column headers to sort
Type Species Molecular location Description Reference
Frameshift Mouse Duplication of exon 5 13
Disease:  Hereditary hyperekplexia
OMIM:  149400
Orphanet:  3197
Role:  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
Click column headers to sort
Type Species Molecular location Description Reference
None Human Around 20 α1 GlyR mutations have been identified to date in ~70 human hyperekplexia pedigrees 2
General Comments
The rat 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. , 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. 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]

21. 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]

22. 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]

23. 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]

24. 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]

25. 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]

26. 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]

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

To cite this database page, please use the following:

Joseph. W. Lynch.
Glycine receptors: α1. Last modified on 18/01/2012. Accessed on 20/05/2013. IUPHAR database (IUPHAR-DB), http://www.iuphar-db.org/DATABASE/ObjectDisplayForward?objectId=423.


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