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Glycine Receptor (All subtypes)

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Target not currently curated in GtoImmuPdb

Target id: 428

Nomenclature: Glycine Receptor (All subtypes)

Family: Glycine receptors

Contents:

Single Channel Conductance of Recombinant Receptors
Recombinant receptor Conductance states (pS) Reference
I II III IV V VI
α1 - 75.0 – 88.0 * 59.0 – 68.0 43.0 – 49.0 25.0 – 30.0 15.0 – 18.0 2,4,31,39
α1β - - - 39.0 – 44.0 * 29.0 20.0 4-5
α2 111.0 * 88.0 – 91.0 * 66.0 – 72.0 * 42.0 – 48.0 24.0 – 36.0 - 4,39
α2β 112.0 80.0 - 54.0 * 36.0 - 4
α3 105.0 * 85.0 62.0 42.0 30.0 20.0 4
α3β - - - 48.0 * 34.0 23.0 4
* the most frequently occurring conductance states
Natural/Endogenous Ligands Click here for help
glycine
taurine
Zn2+

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Agonists
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
ivermectin Small molecule or natural product Approved drug Click here for species-specific activity table Hs Irreversible agonist 6.4 pEC50 34
⤷ pEC50 6.4 [34]
glycine Small molecule or natural product Click here for species-specific activity table Ligand is endogenous in the given species Ligand has a PDB structure Hs Agonist 4.3 – 4.6 pEC50 4,21
⤷ pEC50 4.3 – 4.6 [4,21]
β-alanine Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Partial agonist 4.3 pEC50 21
⤷ pEC50 4.3 [21]
taurine Small molecule or natural product Ligand is endogenous in the given species Ligand has a PDB structure Hs Agonist 3.8 pEC50 21
⤷ pEC50 3.8 [21]
GABA Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Rn Partial agonist 0.0 – 1.2 pEC50 7,33
⤷ pEC50 0.0 – 1.2 [7,33]
View species-specific agonist tables
Agonist Comments
Where possible, EC50 values are given for α1 GlyRs recombinantly expressed in HEK293 cells. Corresponding values are usually several fold higher at Xenopus oocyte-expressed receptors [7,17].
Antagonists
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
[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 8.5 pKd 8,40
⤷ pKd 8.5 [8,40]
[3H]strychnine Small molecule or natural product Ligand is labelled Ligand is radioactive Ligand has a PDB structure Rn Antagonist 8.5 pKd 40
⤷ pKd 8.5 [40]
RU5135 Small molecule or natural product Rn Antagonist 8.5 pKd 6,35
⤷ pKd 8.5 [6,35]
tropisetron Small molecule or natural product Approved drug Click here for species-specific activity table Ligand has a PDB structure Hs Antagonist 4.1 pIC50 24,43
⤷ pIC50 4.1 [24,43]
atropine Small molecule or natural product Approved drug Click here for species-specific activity table Hs Antagonist 3.6 pIC50 24,43
⤷ pIC50 3.6 [24,43]
View species-specific antagonist tables
Antagonist Comments
All chemical compounds named here are condidered to act in as typical classical competitive antagonists.
  • RU 5153 is also reported to affect the cat receptor with a similar pKd value (8.5) to rat [6,35].
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 < 1x10-6 yes 32
⤷ pIC50 5.9 Conc range: < 1x10-6 M [32]
Voltage dependent
picrotoxinin Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs - no 4.6 – 5.3 pIC50 - no 20,30,42
⤷ pIC50 4.6 – 5.3 [20,30,42]
Not voltage dependent
Channel Blocker Comments
Chemical compounds provided are all thought to bind in the channel pore thereby blocking current.
  • Structure-activity analysis of ginkgolide (A, B, C and J) binding in the glycine receptor pore appears to demonstrate selectivity across heteromeric combinations of the subunits [10-11,13] . The gingkolide compounds (A,B,C and J) were all found to act as channel blockers at the glycine receptor with pIC50 values in the range 5.0-6.2 [10-11].
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
ethanol Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Potentiation - - 1x10-2 - 2x10-1 no 27
⤷ Conc range: 1x10-2 - 2x10-1 M Potentiation of weakly activated GlyRs only [27]
Not voltage dependent
Zn2+ Click here for species-specific activity table Ligand is endogenous in the given species Hs Inhibition - - 1x10-5 no 16,19,29
⤷ Conc range: 1x10-5 M [16,19,29]
Not voltage dependent
Zn2+ Click here for species-specific activity table Ligand is endogenous in the given species Hs Potentiation - - 2x10-8 - 1x10-5 no 3,16,19,29
⤷ Conc range: 2x10-8 - 1x10-5 M [3,16,19,29]
Not voltage dependent
Allosteric Modulator Comments
Numerous other positive and negative modulators exist, but most exert effects at other ligand-gated ion channels. Only the most extensively characterised are listed above together with an indication of the range of concentrations over which they are active. See [1] for a more complete review of GlyR molecular pharmacology.
Subunit-specific Pharmacological Agents at Recombinant Receptors
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Action Subunit specificity Concentration range (M) Reference
α-Emtbl Small molecule or natural product Mixed Potentiation: α2, α1β, α3β
inhibition: α3		 > 1x10-4 37
atropine Small molecule or natural product Approved drug Inhibition α2 > α1 < 1x10-6 24
Zn2+ Ligand is endogenous in the given species Inhibition α1, α2 >> α1β, α2β < 1x10-6 28
ginkgolide A Small molecule or natural product Inhibition α2β > α1β < 1x10-6 10
ginkgolide C Small molecule or natural product Inhibition α1β, α2β > α1, α2 < 1x10-6 10
ginkgolide J Small molecule or natural product Inhibition α1β > α1 < 1x10-6 11
picrotoxinin Small molecule or natural product Ligand has a PDB structure Inhibition α2, α3 > α1 >> α1β, α2β ,α3β < 1x10-6 30,42
5,7-dichlorokynurenic acid Small molecule or natural product Ligand has a PDB structure Inhibition α2 > α1 < 1x10-6 9
alkylbenzene sulfonate Small molecule or natural product Inhibition α2 > α1 < 1x10-6 23
bilobalide Small molecule or natural product Inhibition α2 > α1 > α2β > α1β < 1x10-6 10
colchicine Small molecule or natural product Approved drug Ligand has a PDB structure Immunopharmacology Ligand Inhibition α2 > α1 < 1x10-6 22
cyanotriphenylborate Small molecule or natural product Inhibition α1 > α2 < 1x10-6 32
dehydroepiandrosterone Small molecule or natural product Approved drug Ligand has a PDB structure Inhibition α1, α2 > α1β, α2β ,α4 < 1x10-6 25
NBBCC Small molecule or natural product Inhibition α2 > α2β < 1x10-6 26
pregnenolone Small molecule or natural product Approved drug Ligand has a PDB structure Potentiation α1 only, no effect on α2, α1β < 1x10-6 25
progesterone Small molecule or natural product Approved drug Ligand has a PDB structure Inhibition α2 > α1, α1β < 1x10-6 25
tropisetron Small molecule or natural product Approved drug Ligand has a PDB structure Potentiation α1β, α2β , α1, no effect on α2 < 1x10-8 38
Zn2+ Ligand is endogenous in the given species Potentiation α1, α1β > α2, α2β < 1x10-8 29
ginkgolide B Small molecule or natural product Inhibition α1β, α2β > α1, α2 < 1x10-8 10-11
NV-31 Small molecule or natural product Potentiation α1 only, no effect on α2, α3 < 1x10-8 18
anandamide Small molecule or natural product Ligand has a PDB structure Potentiation α1 and α1β only, no effect on α2 or α3 < 1x10-8 41
HU-210 Small molecule or natural product Potentiation α1 only, no potentiation of α3 or α3 < 1x10-6 41
HU-210 Small molecule or natural product Inhibition α3>α2, no inhibition of α1 < 1x10-8 41
WIN55212-2 Small molecule or natural product Ligand has a PDB structure Inhibition α3>α2, no inhibition of α1 < 1x10-6 41
onternabez Small molecule or natural product Inhibition α3>α2>α1 < 1x10-6 41
Subunit-specific Pharmacological Agents at Recombinant Receptors Comments
Please note that the subunit specific pharmacology profiles recorded are not species dependent
Functional Assays Click here for help
Measurement of intracellular chloride concentration change using a single cell imaging system in HEK-293 cells transiently transfected with α1 GlyR subunit and a chloride-sensitive yellow fluorescent protein
Species:  Human
Tissue:  HEK-293 cells
Response measured:  change in fluorescence of chloride sensitive fluorophore
References:  14
Measurement of anion current in Xenopus oocytes expressing α1 GlyR subunit
Species:  Rat
Tissue:  Xenopus laevis oocytes
Response measured:  anion current under voltage-clamp
References:  15
Indirect measurement of membrane potential using a fluorometric plate reader in HEK-293 cells stably transfected with α1 GlyR subunit
Species:  Human
Tissue:  HEK-293 cells
Response measured:  change in fluorescence of voltage sensitive dye
References:  12
Measurement of anion current in HEK-293 cells transfected with α1 GlyR subunit
Species:  Human
Tissue:  HEK-293 cells
Response measured:  anion current under voltage-clamp
References:  4,31,36

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. Beato M, Groot-Kormelink PJ, Colquhoun D, Sivilotti LG. (2002) Openings of the rat recombinant alpha 1 homomeric glycine receptor as a function of the number of agonist molecules bound. J Gen Physiol, 119 (5): 443-66. [PMID:11981023]

3. Bloomenthal AB, Goldwater E, Pritchett DB, Harrison NL. (1994) Biphasic modulation of the strychnine-sensitive glycine receptor by Zn2+. Mol Pharmacol, 46 (6): 1156-9. [PMID:7808436]

4. Bormann J, Rundström N, Betz H, Langosch D. (1993) Residues within transmembrane segment M2 determine chloride conductance of glycine receptor homo- and hetero-oligomers. EMBO J, 12 (10): 3729-37. [PMID:8404844]

5. Burzomato V, Beato M, Groot-Kormelink PJ, Colquhoun D, Sivilotti LG. (2004) Single-channel behavior of heteromeric alpha1beta glycine receptors: an attempt to detect a conformational change before the channel opens. J Neurosci, 24 (48): 10924-40. [PMID:15574743]

6. Curtis DR, Malik R. (1985) Glycine antagonism by RU 5135. Eur J Pharmacol, 110 (3): 383-4. [PMID:4007055]

7. De Saint Jan D, David-Watine B, Korn H, Bregestovski P. (2001) Activation of human alpha1 and alpha2 homomeric glycine receptors by taurine and GABA. J Physiol (Lond.), 535 (Pt 3): 741-55. [PMID:11559772]

8. Grenningloh G, Rienitz A, Schmitt B, Methfessel C, Zensen M, Beyreuther K, Gundelfinger ED, Betz H. (1987) The strychnine-binding subunit of the glycine receptor shows homology with nicotinic acetylcholine receptors. Nature, 328 (6127): 215-20. [PMID:3037383]

9. Han Y, Li P, Slaughter MM. (2004) Selective antagonism of rat inhibitory glycine receptor subunits. J Physiol (Lond.), 554 (Pt 3): 649-58. [PMID:14645455]

10. Hawthorne R, Cromer BA, Ng HL, Parker MW, Lynch JW. (2006) Molecular determinants of ginkgolide binding in the glycine receptor pore. J Neurochem, 98 (2): 395-407. [PMID:16805834]

11. Heads JA, Hawthorne RL, Lynagh T, Lynch JW. (2008) Structure-activity analysis of ginkgolide binding in the glycine receptor pore. J Neurochem, 105 (4): 1418-27. [PMID:18221374]

12. Jensen AA, Kristiansen U. (2004) Functional characterisation of the human alpha1 glycine receptor in a fluorescence-based membrane potential assay. Biochem Pharmacol, 67 (9): 1789-99. [PMID:15081878]

13. Kondratskaya EL, Betz H, Krishtal OA, Laube B. (2005) The beta subunit increases the ginkgolide B sensitivity of inhibitory glycine receptors. Neuropharmacology, 49 (6): 945-51. [PMID:16125206]

14. Kruger W, Gilbert D, Hawthorne R, Hryciw DH, Frings S, Poronnik P, Lynch JW. (2005) A yellow fluorescent protein-based assay for high-throughput screening of glycine and GABAA receptor chloride channels. Neurosci Lett, 380 (3): 340-5. [PMID:15862914]

15. Kuhse J, Schmieden V, Betz H. (1990) Identification and functional expression of a novel ligand binding subunit of the inhibitory glycine receptor. J Biol Chem, 265 (36): 22317-20. [PMID:2176214]

16. Laube B, Kuhse J, Rundström N, Kirsch J, Schmieden V, Betz H. (1995) Modulation by zinc ions of native rat and recombinant human inhibitory glycine receptors. J Physiol (Lond.), 483 ( Pt 3): 613-9. [PMID:7776247]

17. Laube B, Langosch D, Betz H, Schmieden V. (1995) Hyperekplexia mutations of the glycine receptor unmask the inhibitory subsite for beta-amino-acids. Neuroreport, 6 (6): 897-900. [PMID:7542038]

18. Lynch JW, Chen X. (2008) Subunit-specific potentiation of recombinant glycine receptors by NV-31, a bilobalide-derived compound. Neurosci Lett, 435 (2): 147-51. [PMID:18329806]

19. Lynch JW, Jacques P, Pierce KD, Schofield PR. (1998) Zinc potentiation of the glycine receptor chloride channel is mediated by allosteric pathways. J Neurochem, 71 (5): 2159-68. [PMID:9798943]

20. Lynch JW, Rajendra S, Barry PH, Schofield PR. (1995) Mutations affecting the glycine receptor agonist transduction mechanism convert the competitive antagonist, picrotoxin, into an allosteric potentiator. J Biol Chem, 270 (23): 13799-806. [PMID:7775436]

21. Lynch JW, Rajendra S, Pierce KD, Handford CA, Barry PH, Schofield PR. (1997) Identification of intracellular and extracellular domains mediating signal transduction in the inhibitory glycine receptor chloride channel. EMBO J, 16 (1): 110-20. [PMID:9009272]

22. Machu TK. (1998) Colchicine competitively antagonizes glycine receptors expressed in Xenopus oocytes. Neuropharmacology, 37 (3): 391-6. [PMID:9681937]

23. Machu TK, Mihic SJ, Dildy-Mayfield JE. (1998) Selective actions of a detergent on ligand-gated ion channels expressed in Xenopus oocytes. J Pharmacol Exp Ther, 284 (1): 32-6. [PMID:9435157]

24. Maksay G, Laube B, Betz H. (1999) Selective blocking effects of tropisetron and atropine on recombinant glycine receptors. J Neurochem, 73 (2): 802-6. [PMID:10428078]

25. Maksay G, Laube B, Betz H. (2001) Subunit-specific modulation of glycine receptors by neurosteroids. Neuropharmacology, 41 (3): 369-76. [PMID:11522328]

26. Mangin JM, Nguyen L, Gougnard C, Hans G, Rogister B, Belachew S, Moonen G, Legendre P, Rigo JM. (2005) Developmental regulation of beta-carboline-induced inhibition of glycine-evoked responses depends on glycine receptor beta subunit expression. Mol Pharmacol, 67 (5): 1783-96. [PMID:15722459]

27. Mascia MP, Mihic SJ, Valenzuela CF, Schofield PR, Harris RA. (1996) A single amino acid determines differences in ethanol actions on strychnine-sensitive glycine receptors. Mol Pharmacol, 50 (2): 402-6. [PMID:8700149]

28. Miller PS, Beato M, Harvey RJ, Smart TG. (2005) Molecular determinants of glycine receptor alphabeta subunit sensitivities to Zn2+-mediated inhibition. J Physiol (Lond.), 566 (Pt 3): 657-70. [PMID:15905212]

29. Miller PS, Da Silva HM, Smart TG. (2005) Molecular basis for zinc potentiation at strychnine-sensitive glycine receptors. J Biol Chem, 280 (45): 37877-84. [PMID:16144831]

30. Pribilla I, Takagi T, Langosch D, Bormann J, Betz H. (1992) The atypical M2 segment of the beta subunit confers picrotoxinin resistance to inhibitory glycine receptor channels. EMBO J, 11 (12): 4305-11. [PMID:1385113]

31. Rajendra S, Lynch JW, Pierce KD, French CR, Barry PH, Schofield PR. (1995) Mutation of an arginine residue in the human glycine receptor transforms beta-alanine and taurine from agonists into competitive antagonists. Neuron, 14 (1): 169-75. [PMID:7826634]

32. 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]

33. Schmieden V, Kuhse J, Betz H. (1993) Mutation of glycine receptor subunit creates beta-alanine receptor responsive to GABA. Science, 262 (5131): 256-8. [PMID:8211147]

34. Shan Q, Haddrill JL, Lynch JW. (2001) Ivermectin, an unconventional agonist of the glycine receptor chloride channel. J Biol Chem, 276 (16): 12556-64. [PMID:11278873]

35. Simmonds MA, Turner JP. (1985) Antagonism of inhibitory amino acids by the steroid derivative RU5135. Br J Pharmacol, 84 (3): 631-5. [PMID:3986429]

36. 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]

37. Steinbach JH, Bracamontes J, Yu L, Zhang P, Covey DF. (2000) Subunit-specific action of an anticonvulsant thiobutyrolactone on recombinant glycine receptors involves a residue in the M2 membrane-spanning region. Mol Pharmacol, 58 (1): 11-7. [PMID:10860922]

38. Supplisson S, Chesnoy-Marchais D. (2000) Glycine receptor beta subunits play a critical role in potentiation of glycine responses by ICS-205,930. Mol Pharmacol, 58 (4): 763-70. [PMID:10999946]

39. Takahashi T, Momiyama A, Hirai K, Hishinuma F, Akagi H. (1992) Functional correlation of fetal and adult forms of glycine receptors with developmental changes in inhibitory synaptic receptor channels. Neuron, 9 (6): 1155-61. [PMID:1281418]

40. Vandenberg RJ, Handford CA, Schofield PR. (1992) Distinct agonist- and antagonist-binding sites on the glycine receptor. Neuron, 9 (3): 491-6. [PMID:1326295]

41. Yang Z, Aubrey KR, Alroy I, Harvey RJ, Vandenberg RJ, Lynch JW. (2008) Subunit-specific modulation of glycine receptors by cannabinoids and N-arachidonyl-glycine. Biochem Pharmacol, 76 (8): 1014-23. [PMID:18755158]

42. Yang Z, Cromer BA, Harvey RJ, Parker MW, Lynch JW. (2007) A proposed structural basis for picrotoxinin and picrotin binding in the glycine receptor pore. J Neurochem, 103 (2): 580-9. [PMID:17714449]

43. Yang Z, Ney A, Cromer BA, Ng HL, Parker MW, Lynch JW. (2007) Tropisetron modulation of the glycine receptor: femtomolar potentiation and a molecular determinant of inhibition. J Neurochem, 100 (3): 758-69. [PMID:17181559]

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