Glycine Receptors


The inhibitory glycine receptor is a ligand‐gated chloride channel of the cys‐loop receptor family. As a chloride‐selective channel, it mediates rapid synaptic inhibition in mammalian spinal cord, brainstem, higher brain centres and nonneuronal tissues. In recent years, our understanding of glycine receptors has steadily grown, adding considerable depth to our knowledge of receptor function, structure, cellular trafficking and tissue distribution. Furthermore, new roles for glycinergic transmission in higher brain function have been uncovered. Glycine receptors should no longer be considered only as mediators of spinal reflexes, but were also found to play an important role in the modulation of higher brain function, including vision, hearing and pain signalling. The identification of novel agonists and modulators underlines the relevance of the inhibitory glycine receptor as a therapeutic target. This review extends a previous article of this series and highlights key developments in glycine receptor research over the past 2–3 years.

Key Concepts:

  • Glycine receptors are key mediators of rapid synaptic inhibition in mammalian spinal cord and higher brain centres.

  • Glycine receptors are members of the cys‐loop family of ligand‐gated ion channel receptors.

  • Glycinergic signalling is involved in motor control, pain signalling, vision, hearing and other brain functions.

  • Mutations in glycine receptor genes underlie human hyperekplexia and related myoclonic diseases.

  • New modulators of glycine receptor function are rare and of considerable medicinal interest.

Keywords: glycine receptor; ligand‐gated ion channels; cys‐loop receptors; structure–function relationship; inhibitory transmission; tissue distribution; glycine receptor pharmacology; startle disease; mutations; animal models

Figure 1.

Schematic drawing of glycine receptor topology. (a) Side view of receptor complex. (b) Top view of receptor, pore‐lining TM2 is shaded. (c) Topology of one receptor subunit. Secondary structures and mutations in the receptor protein are indicated after modelled structures (see Legendre et al., ; Yevenes and Zeilhofer, ). •, ethanol‐sensitive residues (A52, S267, A288‐TM3, K385/K386); ▪, Zn2+‐sensitive residues (D80, E192, E194); ▴, Tropeine modulation (Q67, R119, S129); ○, Anaesthetic‐sensitive residues (S267, A288‐TM3); □, Ivermectin interaction (A288‐TM3); ◊, THC modulation (S296‐TM3).



Adermark L, Clarke RB, Ericson M and Soderpalm B (2011) Subregion‐specific modulation of excitatory input and dopaminergic output in the striatum by tonically activated glycine and GABA(A) receptors. Frontiers in Systems Neuroscience 5: 85. doi:10.3389/fnsys.2011.00085.

Aroeira RI, Ribeiro JA, Sebastiao AM and Valente CA (2010) Age‐related changes of glycine receptor at the rat hippocampus: from the embryo to the adult. Journal of Neurochemistry 118: 339–353.

Baer K, Waldvogel HJ, Faull RL and Rees MI (2009) Localization of glycine receptors in the human forebrain, brainstem, and cervical spinal cord: an immunohistochemical review. Frontiers in Molecular Neuroscience 2: 25. doi:10.3389/neuro.02.025.2009.

Bode A and Lynch JW (2014) The impact of human hyperekplexia mutations on glycine receptor structure and function. Molecular Brain 7: 2. doi:10.1186/1756-6606-7-2.

Bregestovski P, Waseem T and Mukhtarov M (2009) Genetically encoded optical sensors for monitoring of intracellular chloride and chloride‐selective channel activity. Frontiers in Molecular Neuroscience 2: 15. doi:10.3389/neuro.02.015.2009.

Breitinger HG and Becker CM (2002) The inhibitory glycine receptor‐simple views of a complicated channel. ChemBioChem 3: 1042–1052.

Buerbank S, Becker K, Becker CM et al. (2011) Developmental regulation of glycine receptors at efferent synapses of the murine cochlea. Histochemistry and Cell Biology 136: 387–398.

Butler MH, Hayashi A, Ohkoshi N et al. (2000) Autoimmunity to gephyrin in Stiff‐Man syndrome. Neuron 26: 307–312.

Chang Q and Martin LJ (2011) Glycine receptor channels in spinal motoneurons are abnormal in a transgenic mouse model of amyotrophic lateral sclerosis. Journal of Neuroscience 31: 2815–2827.

Charrier C, Ehrensperger MV, Dahan M, Levi S and Triller A (2006) Cytoskeleton regulation of glycine receptor number at synapses and diffusion in the plasma membrane. Journal of Neuroscience 26: 8502–8511.

Charrier C, Machado P, Tweedie‐Cullen RY et al. (2010) A crosstalk between beta1 and beta3 integrins controls glycine receptor and gephyrin trafficking at synapses. Nature Neuroscience 13: 1388–1395.

Corringer PJ, Baaden M, Bocquet N et al. (2010) Atomic structure and dynamics of pentameric ligand‐gated ion channels: new insight from bacterial homologues. Journal of Physiology 588: 565–572.

Dacosta CJ and Baenziger JE (2013) Gating of pentameric ligand‐gated ion channels: structural insights and ambiguities. Structure 21: 1271–1283.

Davies JS, Chung SK, Thomas RH et al. (2010) The glycinergic system in human startle disease: a genetic screening approach. Frontiers in Molecular Neuroscience 3: 8. doi:10.3389/fnmol.2010.00008.

Dreissen YE and Tijssen MA (2012) The startle syndromes: physiology and treatment. Epilepsia 53 (Suppl 7): 3–11.

Dumoulin A, Triller A and Kneussel M (2009) Cellular transport and membrane dynamics of the glycine receptor. Frontiers in Molecular Neuroscience 2: 28. doi:10.3389/neuro.02.028.2009.

Duret G, Van Renterghem C, Weng Y et al. (2011) Functional prokaryotic‐eukaryotic chimera from the pentameric ligand‐gated ion channel family. Proceedings of the National Academy of Sciences of the USA 108: 12143–12148.

Dutertre S, Becker CM and Betz H (2012) Inhibitory glycine receptors: an update. Journal of Biological Chemistry 287: 40216–40223.

Eichler SA, Forstera B, Smolinsky B et al. (2009) Splice‐specific roles of glycine receptor alpha3 in the hippocampus. European Journal of Neuroscience 30: 1077–1091.

Espay AJ and Chen R (2013) Myoclonus. Continuum (Minneapolis, Minn.) 19: 1264–1286.

den Eynden JV, Ali SS, Horwood N et al. (2009) Glycine and glycine receptor signalling in non‐neuronal cells. Frontiers in Molecular Neuroscience 2: 9. doi:10.3389/neuro.02.009.2009.

Froh M, Thurman RG and Wheeler MD (2002) Molecular evidence for a glycine‐gated chloride channel in macrophages and leukocytes. American Journal of Physiology‐Gastrointestinal and Liver Physiology 283: G856–G863.

Ganser LR and Dallman JE (2009) Glycinergic synapse development, plasticity, and homeostasis in zebrafish. Frontiers in Molecular Neuroscience 2: 30. doi:10.3389/neuro.02.030.2009.

Gilbert DF, Islam R, Lynagh T, Lynch JW and Webb TI (2009) High throughput techniques for discovering new glycine receptor modulators and their binding sites. Frontiers in Molecular Neuroscience 2: 17. doi:10.3389/neuro.02.017.2009.

Haselwandter CA, Calamai M, Kardar M, Triller A and da Silveira RA (2011) Formation and stability of synaptic receptor domains. Physical Review Letters 106: 238104.

Herrera AI, Al‐Rawi A, Cook GA et al. (2010) Structural characterization of two pore‐forming peptides: consequences of introducing a C‐terminal tryptophan. Proteins 78: 2238–2250.

Herweg J and Schwarz G (2012) Splice‐specific glycine receptor binding, folding, and phosphorylation of the scaffolding protein gephyrin. Journal of Biological Chemistry 287: 12645–12656.

Iizuka T, Leite MI, Lang B et al. (2012) Glycine receptor antibodies are detected in progressive encephalomyelitis with rigidity and myoclonus (PERM) but not in saccadic oscillations. Journal of Neurology 259: 1566–1573.

James VM, Gill JL, Topf M and Harvey RJ (2012) Molecular mechanisms of glycine transporter GlyT2 mutations in startle disease. Biological Chemistry 393: 283–289.

Jonsson S, Morud J, Pickering C et al. (2012) Changes in glycine receptor subunit expression in forebrain regions of the Wistar rat over development. Brain Research 1446: 12–21.

Kumar P and Meizel S (2008) Identification and spatial distribution of glycine receptor subunits in human sperm. Reproduction 136: 387–390.

Le‐Corronc H, Rigo JM, Branchereau P and Legendre P (2011) GABA(A) receptor and glycine receptor activation by paracrine/autocrine release of endogenous agonists: more than a simple communication pathway. Molecular Neurobiology 44: 28–52.

Legendre P, Forstera B, Juttner R and Meier JC (2009) Glycine receptors caught between genome and proteome – functional implications of RNA editing and splicing. Frontiers in Molecular Neuroscience 2: 23. doi:10.3389/neuro.02.023.2009.

Lynagh T and Lynch JW (2012) Molecular mechanisms of Cys‐loop ion channel receptor modulation by ivermectin. Frontiers in Molecular Neuroscience 5: 60. doi:10.3389/fnmol.2012.00060.

Lynch JW (2004) Molecular structure and function of the glycine receptor chloride channel. Physiological Reviews 84: 1051–1095.

Lynch JW (2009) Native glycine receptor subtypes and their physiological roles. Neuropharmacology 56: 303–309.

Lynch JW and Callister RJ (2006) Glycine receptors: a new therapeutic target in pain pathways. Current Opinion in Investigational Drugs 7: 48–53.

Moroni M, Meyer JO, Lahmann C and Sivilotti LG (2011) In glycine and GABA(A) channels, different subunits contribute asymmetrically to channel conductance via residues in the extracellular domain. Journal of Biological Chemistry 286: 13414–13422.

Mullins JG, Chung SK and Rees MI (2010) Fine architecture and mutation mapping of human brain inhibitory system ligand gated ion channels by high‐throughput homology modeling. Advances in Protein Chemistry and Structural Biology 80: 117–152.

Pless SA, Hanek AP, Price KL et al. (2011) A cation‐pi interaction at a phenylalanine residue in the glycine receptor binding site is conserved for different agonists. Molecular Pharmacology 79: 742–748.

Ren J and Greer JJ (2008) Modulation of perinatal respiratory rhythm by GABA(A)‐ and glycine receptor‐mediated chloride conductances. Advances in Experimental Medicine and Biology 605: 149–153.

Schaefer N, Langlhofer G, Kluck CJ and Villmann C (2013) Glycine receptor mouse mutants: model systems for human hyperekplexia. British Journal of Pharmacology 170: 933–952.

Sivilotti LG (2010) What single‐channel analysis tells us of the activation mechanism of ligand‐gated channels: the case of the glycine receptor. Journal of Physiology 588: 45–58.

Sommerhage F, Baumann A, Wrobel G, Ingebrandt S and Offenhausser A (2010) Extracellular recording of glycine receptor chloride channel activity as a prototype for biohybrid sensors. Biosensors & Bioelectronics 26: 155–161.

Talwar S and Lynch JW (2014) Phosphorylation mediated structural and functional changes in pentameric ligand‐gated ion channels: implications for drug discovery. International Journal of Biochemistry & Cell Biology 53C: 218–223.

Todorovic J, Welsh BT, Bertaccini EJ, Trudell JR and Mihic SJ (2010) Disruption of an intersubunit electrostatic bond is a critical step in glycine receptor activation. Proceedings of the National Academy of Sciences of the USA 107: 7987–7992.

Tretter V, Mukherjee J, Maric HM et al. (2012) Gephyrin, the enigmatic organizer at GABAergic synapses. Frontiers in Cellular Neuroscience 6: 23. doi:10.3389/fncel.2012.00023.

Unwin N (2013) Nicotinic acetylcholine receptor and the structural basis of neuromuscular transmission: insights from Torpedo postsynaptic membranes. Quarterly Reviews of Biophysics 46: 283–322.

Wang H, Turner JG, Ling L et al. (2009) Age‐related changes in glycine receptor subunit composition and binding in dorsal cochlear nucleus Neuroscience 160: 227–239.

Wang HD, Lu XX, Lu DX et al. (2009) Glycine inhibits the LPS‐induced increase in cytosolic Ca2+ concentration and TNFalpha production in cardiomyocytes by activating a glycine receptor. Acta Pharmacologica Sinica 30: 1107–1114.

Wang Q and Lynch JW (2011) Activation and desensitization induce distinct conformational changes at the extracellular‐transmembrane domain interface of the glycine receptor. Journal of Biological Chemistry 286: 38814–38824.

Wassle H, Heinze L, Ivanova E et al. (2009) Glycinergic transmission in the mammalian retina. Frontiers in Molecular Neuroscience 2: 6. doi:10.3389/neuro.02.006.2009.

Weltzien F, Puller C, O'Sullivan GA, Paarmann I and Betz H (2012) Distribution of the glycine receptor beta‐subunit in the mouse CNS as revealed by a novel monoclonal antibody. Journal of Comparative Neurology 520: 3962–3981.

Yardley MM, Wyatt L, Khoja S et al. (2012) Ivermectin reduces alcohol intake and preference in mice. Neuropharmacology 63: 190–201.

Ye ZY, Lu YG, Sun H et al. (2008) Fluoxetine inhibition of glycine receptor activity in rat hippocampal neurons. Brain Research 1239: 77–84.

Yevenes GE and Zeilhofer HU (2011) Allosteric modulation of glycine receptors. British Journal of Pharmacology 164: 224–236.

Yim PD, Gallos G, Xu D, Zhang Y and Emala CW (2011) Novel expression of a functional glycine receptor chloride channel that attenuates contraction in airway smooth muscle. FASEB Journal 25: 1706–1717.

Zeilhofer HU, Wildner H and Yevenes GE (2012) Fast synaptic inhibition in spinal sensory processing and pain control. Physiological Reviews 92: 193–235.

Zhang C and McCall MA (2012) Receptor targets of amacrine cells. Visual Neuroscience 29: 11–29.

Zhang L and Xiong W (2009) Modulation of the Cys‐loop ligand‐gated ion channels by fatty acid and cannabinoids. Vitamins & Hormones 81: 315–335.

Further Reading

Balansa W, Islam R, Fontaine F et al. (2010) Ircinialactams: subunit‐selective glycine receptor modulators from Australian sponges of the family Irciniidae. Bioorganic & Medicinal Chemistry 18: 2912–2919.

Duan L, Yang J and Slaughter MM (2009) Caffeine inhibition of ionotropic glycine receptors. Journal of Physiology 587: 4063–4075.

Fuentealba J, Munoz B, Yevenes G et al. (2011) Potentiation and inhibition of glycine receptors by tutin. Neuropharmacology 60: 453–459.

Islam R and Lynch JW (2012) Mechanism of action of the insecticides, lindane and fipronil, on glycine receptor chloride channels. British Journal of Pharmacology 165: 2707–2720.

Jensen AA, Begum N, Vogensen SB et al. (2007) Probing the pharmacophore of ginkgolides as glycine receptor antagonists. Journal of Medicinal Chemistry 50: 1610–1617.

Liu J, Wu DC and Wang YT (2010) Allosteric potentiation of glycine receptor chloride currents by glutamate. Nature Neuroscience 13: 1225–1232.

Raafat K, Breitinger U, Mahran L, Ayoub N and Breitinger HG (2010) Synergistic inhibition of glycinergic transmission in vitro and in vivo by flavonoids and strychnine. Toxicological Sciences 118: 171–182.

Tipps ME, Lawshe JE, Ellington AD and Mihic SJ (2010) Identification of novel specific allosteric modulators of the glycine receptor using phage display. Journal of Biological Chemistry 285: 22840–22845.

Ziegler E, Bodusch M, Song Y et al. (2009) Interaction of androsterone and progesterone with inhibitory ligand‐gated ion channels: a patch clamp study. Naunyn‐Schmiedeberg's Archives of Pharmacology 380: 277–291.

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How to Cite close
Breitinger, Hans‐Georg(Oct 2014) Glycine Receptors. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0000236.pub2]