Glycine receptors | Ion channels | IUPHAR/BPS Guide to MALARIA PHARMACOLOGY

Glycine receptors C

Unless otherwise stated all data on this page refer to the human proteins. Gene information is provided for human (Hs), mouse (Mm) and rat (Rn).

Overview

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The inhibitory glycine receptor (nomenclature as agreed by the NC-IUPHAR Subcommittee on Glycine Receptors) is a member of the Cys-loop superfamily of transmitter-gated ion channels that includes the GABA_A, nicotinic acetylcholine and 5-HT₃ receptors and Zn²⁺- activated channels. The glycine receptor is expressed either as a homo-pentamer of α subunits, or a complex of 4α and 1β subunits [38], that contains an intrinsic anion channel. Four differentially expressed isoforms of the α-subunit (α1-α4) and one variant of the β-subunit (β1, GLRB, P48167) have been identified by genomic and cDNA cloning. Further diversity originates from alternative splicing of the primary gene transcripts for α1 (α1^INS and α1^del), α2 (α2A and α2B), α3 (α3S and α3L) and β (βΔ7) subunits and by mRNA editing of the α2 and α3 subunit [4,21,26]. Both α2 splicing and α3 mRNA editing can produce subunits (i.e., α2B and α3P185L) with enhanced agonist sensitivity. Predominantly, the adult form of the receptor contains α1 (or α3) and β subunits whereas the immature form is mostly composed of only α2 subunits [19]. The α4 subunit is a pseudogene in humans [15]. High resolution molecular structures are available for α1 homomeric, α3 homomeric, and αβ hteromeric receptors in a variety of ligand-induced conformations [3,3,10-12,37]. As in other Cys-loop receptors, the orthosteric binding site for agonists and the competitive antagonist strychnine is formed at the interfaces between the subunits’ extracellular domains. Inclusion of the β-subunit in the pentameric glycine receptor contributes to agonist binding, reduces single channel conductance and alters pharmacology. The β-subunit also anchors the receptor, via an amphipathic sequence within the large intracellular loop region, to gephyrin. This a cytoskeletal attachment protein that binds to a number of subsynaptic proteins involved in cytoskeletal structure and thus clusters and anchors hetero-oligomeric receptors to the synapse [13,24]. G protein βγ subunits enhance the open state probability of native and recombinant glycine receptors by association with domains within the large intracellular loop [34-35]. Intracellular chloride concentration modulates the kinetics of native and recombinant glycine receptors [27]. Intracellular Ca²⁺ appears to increase native and recombinant glycine receptor affinity, prolonging channel open events, by a mechanism that does not involve phosphorylation [5]. Extracellular Zn²⁺ potentiates GlyR function at nanomolar concentrations [23]. and causes inhibition at higher micromolar concentrations (17).

Channels and Subunits

Complexes

Glycine Receptor (All subtypes) Show summary »« Hide summary More detailed page go icon to follow link

Subunits

glycine receptor α1 subunit C Show summary »« Hide summary More detailed page go icon to follow link

Target Id

423

Nomenclature

glycine receptor α1 subunit

Previous and unofficial names

GLYRA1 | glycine receptor strychnine-binding subunit | STHE | glycine receptor

Genes

GLRA1 (Hs), Glra1 (Mm), Glra1 (Rn)

Ensembl ID

ENSG00000145888 (Hs), ENSMUSG00000000263 (Mm), ENSRNOG00000013588 (Rn)

UniProtKB AC

P23415 (Hs), Q64018 (Mm), P07727 (Rn)

Selective agonists (potency order)

glycine > β-alanine > taurine

Selective antagonists

pregnenolone sulphate pK_i 5.7

tropisetron pK_i 4.1

ginkgolide X pIC₅₀ 6.1

nifedipine pIC₅₀ 5.5

bilobalide pIC₅₀ 4.7

colchicine pIC₅₀ 3.5

strychnine

onternabez (weak inhibition)

PMBA

Channel blockers

cyanotriphenylborate pIC₅₀ 5.9 [28]

ginkgolide B pIC₅₀ 5.1 – 6.2

picrotoxinin pIC₅₀ 5.3

picrotin pIC₅₀ 5.3

picrotoxin pIC₅₀ 5.2

Endogenous allosteric modulators

Zn²⁺ (Potentiation) pEC₅₀ 7.4 (endogenous; not affected by β subunit co-expression)

Cu²⁺ (Inhibition) pIC₅₀ 4.8 – 5.4 (endogenous; not affected by β subunit co-expression)

Zn²⁺ (Inhibition) pIC₅₀ 4.8 (endogenous)

Extracellular H⁺ (Inhibition) (endogenous)

Selective allosteric modulators

anandamide (Potentiation) pEC₅₀ 7.4

HU-210 (Potentiation) pEC₅₀ 6.6

Δ⁹-tetrahydrocannabinol (Potentiation) pEC₅₀ ~5.5 (~1500% potentiation)

Labelled ligands

[³H]strychnine (Antagonist)

Functional characteristics

γ = 86 pS (main state); (+ β = 44 pS)

glycine receptor α2 subunit C Show summary »« Hide summary More detailed page go icon to follow link

glycine receptor α3 subunit C Show summary »« Hide summary More detailed page go icon to follow link

glycine receptor α4 subunit (pseudogene in humans) C Show summary »« Hide summary More detailed page go icon to follow link

glycine receptor β subunit C Show summary »« Hide summary More detailed page go icon to follow link

Target Id

427

Nomenclature

glycine receptor β subunit

Previous and unofficial names

spa | glycine receptor

Genes

GLRB (Hs), Glrb (Mm), Glrb (Rn)

Ensembl ID

ENSG00000109738 (Hs), ENSMUSG00000028020 (Mm), ENSRNOG00000010199 (Rn)

UniProtKB AC

P48167 (Hs), P48168 (Mm), P20781 (Rn)

Selective antagonists

tropisetron pK_i 5.3 (when co-expressed with the α2 subunit)

pregnenolone sulphate pK_i 5.6 (when co-expressed with the α1 subunit) , 5.0 (when co-expressed with the α2 subunit)

nifedipine pIC₅₀ 5.9 (when co-expressed with the α1 subunit) , 4.9 (when co-expressed with the α3 subunit)

bilobalide pIC₅₀ 4.3 (when co-expressed with the α2 subunit) , 3.7 (when co-expressed with the α1 subunit)

ginkgolide X pIC₅₀ >3.5 (when co-expressed with the α2 subunit) , >3.5 (when co-expressed with the α1 subunit)

Channel blockers

ginkgolide B pIC₅₀ 6.1 – 6.9 (when co-expressed with the α2 subunit) , 6.3 (when co-expressed with the α3 subunit) , 5.6 – 6.7 (when co-expressed with the α1 subunit)

cyanotriphenylborate pIC₅₀ 5.6 (when co-expressed with the human α1 subunit) [28], 5.1 (when co-expressed with the human α2 subunit) [28] - Rat

picrotoxinin pIC₅₀ 5.1 (when co-expressed with the α3 subunit) , 4.6 (when co-expressed with the α1 subunit)

picrotin pIC₅₀ 4.6 (when co-expressed with the α1 subunit) , 4.6 (when co-expressed with the α3 subunit)

picrotoxin pIC₅₀ 4.5 (when co-expressed with the α2 subunit) , 3.7 (when co-expressed with the α1 subunit)

Endogenous allosteric modulators

Zn²⁺ (Inhibition) pIC₅₀ 4.9 (endogenous; when co-expressed with the α1 subunit) , 3.7 (endogenous; when co-expressed with the α2 subunit)

Comment

Ligand interaction data for hetero-oligomer receptors containing the β subunit are also listed under the α subunit

Comments

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Data in the table refer to homo-oligomeric assemblies of the α-subunit, significant changes introduced by co-expression of the β1 subunit are indicated in parenthesis. Not all glycine receptor ligands are listed within the table, but some that may be useful in distinguishing between glycine receptor isoforms are indicated (see detailed view pages for each subunit: α1, α2, α3, α4, β ). Pregnenolone sulphate, tropisetron and colchicine, for example, although not selective antagonists of glycine receptors, are included for this purpose. Strychnine is a potent and selective competitive glycine receptor antagonist with affinities in the range 5-15 nM. RU5135 demonstrates comparable potency, but additionally blocks GABA_A receptors. There are conflicting reports concerning the ability of cannabinoids to inhibit [16], or potentiate and at high concentrations activate [1-2,6,30-31] glycine receptors. Nonetheless, cannabinoid analogues may hold promise in distinguishing between glycine receptor subtypes [31]. In addition, potentiation of glycine receptor activity by cannabinoids has been claimed to contribute to cannabis-induced analgesia relying on Ser296/307 (α1/α3) in M3 [30]. Several analogues of muscimol and piperidine act as agonists and antagonists of both glycine and GABA_Areceptors. Picrotoxin acts as an allosteric inhibitor that appears to bind within the pore, and shows strong selectivity towards homomeric receptors. While its components, picrotoxinin and picrotin, have equal potencies at α1 receptors, their potencies at α2 and α3 receptors differ modestly and may allow some distinction between different receptor types [32]. Binding of picrotoxin within the pore has been demonstrated in the crystal structure of the related C. elegans GluCl Cys-loop receptor [7]. In addition to the compounds listed in the table, numerous agents act as allosteric regulators of glycine receptors (comprehensively reviewed in [14,17,29,36]). Zn²⁺ acts through distinct binding sites of high- and low-affinity to allosterically enhance channel function at low (<10 µM) concentrations and inhibits responses at higher concentrations in a subunit selective manner [22]. The effect of Zn²⁺ is somewhat mimicked by Ni²⁺. Endogenous Zn²⁺ is essential for normal glycinergic neurotransmission mediated by α1 subunit-containing receptors [8]. Elevation of intracellular Ca²⁺ produces fast potentiation of glycine receptor-mediated responses. Dideoxyforskolin (4 µM) and tamoxifen (0.2–5 µM) both potentiate responses to low glycine concentrations (15 µM), but act as inhibitors at higher glycine concentrations (100 µM). Additional modulatory agents that enhance glycine receptor function include inhalational, and several intravenous general anaesthetics (e.g. minaxolone, propofol and pentobarbitone) and certain neurosteroids. Ethanol and higher order n-alcohols also enhance glycine receptor function although whether this occurs by a direct allosteric action at the receptor [20], or through βγ subunits [33] is debated. Recent crystal structures of the bacterial homologue, GLIC, have identified transmembrane binding pockets for both anaesthetics [25] and alcohols [9]. Solvents inhaled as drugs of abuse (e.g. toluene, 1-1-1-trichloroethane) may act at sites that overlap with those recognising alcohols and volatile anaesthetics to produce potentiation of glycine receptor function. The function of glycine receptors formed as homomeric complexes of α1 or α2 subunits, or hetero-oligomers of α1/β or α2/β subunits, is differentially affected by the 5-HT₃ receptor antagonist tropisetron (ICS 205-930) which may evoke potentiation (which may occur within the femtomolar range at the homomeric glycine α1 receptor), or inhibition, depending upon the subunit composition of the receptor and the concentrations of the modulator and glycine employed. Potentiation and inhibition by tropeines involves different binding modes [18]. Additional tropeines, including atropine, modulate glycine receptor activity.

References

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1. Ahrens J, Demir R, Leuwer M, de la Roche J, Krampfl K, Foadi N, Karst M, Haeseler G. (2009) The nonpsychotropic cannabinoid cannabidiol modulates and directly activates alpha-1 and alpha-1-Beta glycine receptor function. Pharmacology, 83 (4): 217-22. [PMID:19204413]

2. Demir R, Leuwer M, de la Roche J, Krampfl K, Foadi N, Karst M, Dengler R, Haeseler G, Ahrens J. (2009) Modulation of glycine receptor function by the synthetic cannabinoid HU210. Pharmacology, 83 (5): 270-4. [PMID:19307742]

3. Du J, Lü W, Wu S, Cheng Y, Gouaux E. (2015) Glycine receptor mechanism elucidated by electron cryo-microscopy. Nature, 526 (7572): 224-9. [PMID:26344198]

4. Eichler SA, Kirischuk S, Jüttner R, Schafermeier PK, Legendre P, Lehmann TN, Gloveli T, Grantyn R, Meier JC. (2008) Glycinergic tonic inhibition of hippocampal neurons with depolarizing GABAergic transmission elicits histopathological signs of temporal lobe epilepsy. J Cell Mol Med, 12 (6B): 2848-66. [PMID:19210758]

5. Fucile S, De Saint Jan D, de Carvalho LP, Bregestovski P. (2000) Fast potentiation of glycine receptor channels of intracellular calcium in neurons and transfected cells. Neuron, 28 (2): 571-83. [PMID:11144365]

6. Hejazi N, Zhou C, Oz M, Sun H, Ye JH, Zhang L. (2006) Delta9-tetrahydrocannabinol and endogenous cannabinoid anandamide directly potentiate the function of glycine receptors. Mol Pharmacol, 69 (3): 991-7. [PMID:16332990]

7. Hibbs RE, Gouaux E. (2011) Principles of activation and permeation in an anion-selective Cys-loop receptor. Nature, 474 (7349): 54-60. [PMID:21572436]

8. 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]

9. Howard RJ, Murail S, Ondricek KE, Corringer PJ, Lindahl E, Trudell JR, Harris RA. (2011) Structural basis for alcohol modulation of a pentameric ligand-gated ion channel. Proc Natl Acad Sci USA, 108 (29): 12149-54. [PMID:21730162]

10. Huang X, Chen H, Michelsen K, Schneider S, Shaffer PL. (2015) Crystal structure of human glycine receptor-α3 bound to antagonist strychnine. Nature, 526 (7572): 277-80. [PMID:26416729]

11. Huang X, Chen H, Shaffer PL. (2017) Crystal Structures of Human GlyRα3 Bound to Ivermectin. Structure, 25 (6): 945-950.e2. [PMID:28479061]

12. Huang X, Shaffer PL, Ayube S, Bregman H, Chen H, Lehto SG, Luther JA, Matson DJ, McDonough SI, Michelsen K et al.. (2017) Crystal structures of human glycine receptor α3 bound to a novel class of analgesic potentiators. Nat Struct Mol Biol, 24 (2): 108-113. [PMID:27991902]

13. Kirsch J. (2006) Glycinergic transmission. Cell Tissue Res, 326 (2): 535-40. [PMID:16807723]

14. Laube B, Maksay G, Schemm R, Betz H. (2002) Modulation of glycine receptor function: a novel approach for therapeutic intervention at inhibitory synapses?. Trends Pharmacol Sci, 23 (11): 519-27. [PMID:12413807]

15. Leacock S, Syed P, James VM, Bode A, Kawakami K, Keramidas A, Suster M, Lynch JW, Harvey RJ. (2018) Structure/Function Studies of the α4 Subunit Reveal Evolutionary Loss of a GlyR Subtype Involved in Startle and Escape Responses. Front Mol Neurosci, 11: 23. [PMID:29445326]

16. Lozovaya N, Yatsenko N, Beketov A, Tsintsadze T, Burnashev N. (2005) Glycine receptors in CNS neurons as a target for nonretrograde action of cannabinoids. J Neurosci, 25 (33): 7499-506. [PMID:16107637]

17. Lynch JW. (2004) Molecular structure and function of the glycine receptor chloride channel. Physiol Rev, 84 (4): 1051-95. [PMID:15383648]

18. Maksay G, Laube B, Schemm R, Grudzinska J, Drwal M, Betz H. (2009) Different binding modes of tropeines mediating inhibition and potentiation of alpha1 glycine receptors. J Neurochem, 109 (6): 1725-32. [PMID:19383091]

19. 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]

20. Mascia MP, Trudell JR, Harris RA. (2000) Specific binding sites for alcohols and anesthetics on ligand-gated ion channels. Proc Natl Acad Sci USA, 97 (16): 9305-10. [PMID:10908659]

21. Meier JC, Henneberger C, Melnick I, Racca C, Harvey RJ, Heinemann U, Schmieden V, Grantyn R. (2005) RNA editing produces glycine receptor alpha3(P185L), resulting in high agonist potency. Nat Neurosci, 8 (6): 736-44. [PMID:15895087]

22. 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]

23. 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]

24. Moss SJ, Smart TG. (2001) Constructing inhibitory synapses. Nat Rev Neurosci, 2 (4): 240-50. [PMID:11283747]

25. Nury H, Van Renterghem C, Weng Y, Tran A, Baaden M, Dufresne V, Changeux JP, Sonner JM, Delarue M, Corringer PJ. (2011) X-ray structures of general anaesthetics bound to a pentameric ligand-gated ion channel. Nature, 469 (7330): 428-31. [PMID:21248852]

26. Oertel J, Villmann C, Kettenmann H, Kirchhoff F, Becker CM. (2007) A novel glycine receptor beta subunit splice variant predicts an unorthodox transmembrane topology. Assembly into heteromeric receptor complexes. J Biol Chem, 282 (5): 2798-807. [PMID:17145751]

27. Pitt SJ, Sivilotti LG, Beato M. (2008) High intracellular chloride slows the decay of glycinergic currents. J Neurosci, 28 (45): 11454-67. [PMID:18987182]

28. 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]

29. Webb TI, Lynch JW. (2007) Molecular pharmacology of the glycine receptor chloride channel. Curr Pharm Des, 13 (23): 2350-67. [PMID:17692006]

30. Xiong W, Cheng K, Cui T, Godlewski G, Rice KC, Xu Y, Zhang L. (2011) Cannabinoid potentiation of glycine receptors contributes to cannabis-induced analgesia. Nat Chem Biol, 7 (5): 296-303. [PMID:21460829]

31. 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]

32. 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]

33. Yevenes GE, Moraga-Cid G, Avila A, Guzmán L, Figueroa M, Peoples RW, Aguayo LG. (2010) Molecular requirements for ethanol differential allosteric modulation of glycine receptors based on selective Gbetagamma modulation. J Biol Chem, 285 (39): 30203-13. [PMID:20647311]

34. Yevenes GE, Moraga-Cid G, Guzmán L, Haeger S, Oliveira L, Olate J, Schmalzing G, Aguayo LG. (2006) Molecular determinants for G protein betagamma modulation of ionotropic glycine receptors. J Biol Chem, 281 (51): 39300-7. [PMID:17040914]

35. Yevenes GE, Peoples RW, Tapia JC, Parodi J, Soto X, Olate J, Aguayo LG. (2003) Modulation of glycine-activated ion channel function by G-protein betagamma subunits. Nat Neurosci, 6 (8): 819-24. [PMID:12858180]

36. Yevenes GE, Zeilhofer HU. (2011) Allosteric modulation of glycine receptors. Br J Pharmacol, 164 (2): 224-36. [PMID:21557733]

37. Yu J, Zhu H, Lape R, Greiner T, Du J, Lü W, Sivilotti L, Gouaux E. (2021) Mechanism of gating and partial agonist action in the glycine receptor. Cell, 184 (4): 957-968.e21. [PMID:33567265]

38. Zhu H, Gouaux E. (2021) Architecture and assembly mechanism of native glycine receptors. Nature, 599 (7885): 513-517. [PMID:34555840]

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Alexander SPH, Mathie AA, Peters JA, Veale EL, Striessnig J, Kelly E, Armstrong JF, Faccenda E, Harding SD, Davies JA et al. (2023) The Concise Guide to PHARMACOLOGY 2023/24: Ion channels. Br J Pharmacol. 180 Suppl 2:S145-S222.

Glycine receptors C

Overview

Channels and Subunits

Complexes

Subunits

Comments

Further reading

References

NC-IUPHAR subcommittee and family contributors

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