Glycine Receptors

Absract

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).

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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. http://www.els.net [doi: 10.1002/9780470015902.a0000236.pub2]