α1

Nomenclature: α1

Family: Glycine receptors

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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 26
Previous and Unofficial Names
STHE
glycine receptor, alpha 1 (startle disease/hyperekplexia)
startle disease/hyperekplexia
stiff person syndrome
nmf11
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
B230397M16Rik
spd
Database Links
ChEMBL Target
DrugBank Target
Ensembl Gene
Entrez Gene
GeneCards
GenitoUrinary Development Molecular Anatomy Project
HomoloGene
Human Protein Reference Database
InterPro
KEGG Gene
OMIM
Orphanet Gene
PharmGKB Gene
PhosphoSitePlus
Protein Ontology (PRO)
RefSeq Nucleotide
RefSeq Protein
TreeFam
UniGene Hs.
UniProtKB
Wikipedia
Functional Characteristics
γ = 86 pS (main state); (+ β = 44 pS)
Natural/Endogenous Ligands
glycine
Selective agonists (potency order) (Human)
glycine > β-alanine > taurine
Antagonists
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Affinity Units Reference
pregnenolone sulphate Hs Antagonist 5.7 pKi
pKi 5.7 (Ki 1.9x10-6 M)
tropisetron Hs Antagonist 4.1 pKi
pKi 4.1 (Ki 8.4x10-5 M)
ginkgolide X Hs Antagonist 6.1 pIC50
pIC50 6.1 (IC50 7.6x10-7 M)
nifedipine Hs Antagonist 5.5 pIC50
pIC50 5.5 (IC50 3.3x10-6 M)
bilobalide Hs Antagonist 4.7 pIC50
pIC50 4.7 (IC50 2x10-5 M)
colchicine Hs Antagonist 3.5 pIC50
pIC50 3.5 (IC50 3.24x10-4 M)
HU-308 Hs Antagonist - -
weak inhibition
strychnine Hs Antagonist - -
PMBA Hs Antagonist - -
[3H]strychnine Hs Antagonist - -
Channel Blockers
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Use-dependent Affinity Units Concentration range (M) Voltage-dependent (mV) Reference
cyanotriphenylborate Hs - no 5.9 pIC50 - no 20
pIC50 5.9 (IC50 1.3x10-6 M) [20]
Not voltage dependent
ginkgolide B Hs - no 5.1 – 6.2 pIC50 - no
pIC50 5.1 – 6.2 (IC50 6x10-7 – 8x10-6 M)
Not voltage dependent
picrotoxinin Hs - no 5.3 pIC50 - no
pIC50 5.3 (IC50 5.1x10-6 M)
Not voltage dependent
picrotin Hs - no 5.3 pIC50 - no
pIC50 5.3 (IC50 5.2x10-6 M)
Not voltage dependent
picrotoxin 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 Affinity Units Concentration range (M) Voltage-dependent (mV) Reference
anandamide Hs Potentiation 7.4 pEC50 - no
pEC50 7.4 (EC50 3.8x10-8 M)
Not voltage dependent
Zn2+ 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
HU-210 Hs Potentiation 6.6 pEC50 - no
pEC50 6.6 (EC50 2.7x10-7 M)
Not voltage dependent
Δ9-tetrahydrocannabinol Hs Potentiation ~5.5 pEC50 - no
pEC50 ~5.5 (EC50 ~3x10-6 M) ~1500% potentiation
Not voltage dependent
Cu2+ Hs Inhibition 4.8 – 5.4 pIC50 - no
pIC50 4.8 – 5.4 (IC50 4x10-6 – 1.5x10-5 M) endogenous; not affected by β subunit co-expression
Not voltage dependent
Zn2+ Hs Inhibition 4.8 pIC50 - no
pIC50 4.8 (IC50 1.5x10-5 M) endogenous
Not voltage dependent
Extracellular H+ Hs Inhibition - - - no
endogenous
Not voltage dependent
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:  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
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:  Hereditary hyperekplexia
OMIM:  149400
Orphanet:  3197
Role: 
Drugs: 
Comments: 
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
Biologically Significant Variants
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.
Change:  A52S
References:  21,25
Type:  Deletion
Species:  Mouse
Description:  Oscillator mice have a deletion of 7 nucelotides 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.
Change:  A premature stop codon in the α1 GlyR large intracellular domain.
References:  3,14
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.
Change:  Duplication of exon 5
References:  13
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. Neuroscience25 (2): 613-24. [PMID:2840602]

2. Bakker MJ, van Dijk JG, van den Maagdenberg AM, Tijssen MA. (2006) Startle syndromes. Lancet neurology5 (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. Neuron52 (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). Genetics174 (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. Neuroscience78 (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. Neuroscience17 (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. U.S.A.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. Neuroscience43 (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. Neuron2 (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]

How to cite this page

Joseph. W. Lynch.
Glycine receptors: α1. Last modified on 16/05/2014. Accessed on 30/09/2014. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=423.