Glycine receptors: Introduction

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General

The glycine receptor Cl- channel (GlyR) is classically known for mediating inhibitory synaptic transmission between interneurons and motor neurons in reflex circuits of the spinal cord. Glycine was originally proposed as an inhibitory neurotransmitter based on an analysis of its distribution in the spinal cord [1]. Subsequent experiments showed that it activated a strychnine-sensitive inhibitory Cl- conductance in spinal cord neurons [3,14]. Purification of the GlyR from rat spinal cord by strychnine affinity chromatography revealed three distinct polypeptides of molecular mass 48, 58 and 98 kDa [10]. The 48 and 58 kDa peptides were later shown to correspond to the α1 and β subunits, respectively. Cloning of the α1 GlyR subunit was reported in 1987 [5] and its homology with the nicotinic acetylcholine receptor led to its inclusion in the Cys-loop family of ligand-gated ion channel receptors. The α2, α3 and α4 subunits, as well as several splice variants, were subsequently cloned by homology screening [8]. GlyRs are now known to mediate inhibitory neurotransmission in the spinal cord, brainstem and retina. They are also found pre-synaptically, where they modulate neurotransmitter release. Non-synaptic GlyRs exist in neurons in most parts of the brain, as well as in sperm and macrophages. GlyRs conduct monovalent halide anions in a non-selective manner and exhibit unitary conductances of 40-90 pS.

Structure

GlyRs comprise pentameric oligomers with each of the five subunits arranged symmetrically around a central ion-conducting pore. By analogy with the known structures of other Cys-loop family members [2,7,9], each GlyR subunit comprises a large extracellular amino-terminal domain that harbours the ligand binding sites which connects to a bundle of four α-helical transmembrane segments (termed M1 – M4) with a large intracellular domain between M3 and M4. Each of the five subunits contributes an amphipathic M2 domain to the lining of the central water-filled pore [7,9]. All four α subunits (α1-α4) express robustly as homomeric GlyRs in vitro, although β subunits express only as αβ heteromers with a putative 2α:3β stoichiometric ratio [6]. The β subunit serves the important role of anchoring GlyRs to postsynaptic densities via the cytoplasmic clustering protein, gephyrin [4]. Homomeric α1, α3 and α4 GlyRs are weakly expressed at all developmental stages, although homomeric α2 GlyRs are abundantly expressed in embryonic neurons only. The majority of glycinergic neurotransmission in adults is mediated by heteromeric α1&beta GlyRs.

Pharmacology

The rank order potency of amino acid agonists at GlyRs is glycine > β-alanine > taurine. The only non-peptidic agonist identified so far is ivermectin [12]. GlyRs are potently and selectively antagonised by the classical competitive antagonist, strychnine. Although many compounds exhibit modest subunit-specific pharmacological differences at GlyRs [13] to date there are few substances with sufficient discriminatory capacity to identify the presence of α1, α2, and α3 subunits in either homomeric or heteromeric GlyRs. Although picrotoxin distinguishes strongly between α homomeric and αβ heteromeric GlyRs [11] and synthetic cannabinoid agonists (WIN55212-2, HU210 and HU308) distinguish α1 from α2 or α3 containing GlyRs [15], unfortunately all these agents also have potent effects on other receptor types, which limits their utility as probes for establishing the physiological role of different GlyR subtypes. There is thus abundant scope for the development of novel GlyR-specific agents as both therapeutic leads for movement disorders and chronic inflammatory pain and as subunit-specific pharmacological probes for basic research.

References

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1. Aprison MH, Werman R. (1965) The distribution of glycine in cat spinal cord and roots. Life Sci., 4 (21): 2075-83. [PMID:5866625]

2. Brejc K, van Dijk WJ, Smit AB, Sixma TK. (2002) The 2.7 A structure of AChBP, homologue of the ligand-binding domain of the nicotinic acetylcholine receptor. Novartis Found. Symp., 245: 22-9; discussion 29-32, 165-8. [PMID:12027010]

3. Curtis DR, Hösli L, Johnston GA. (1967) Inhibition of spinal neurons by glycine. Nature, 215 (5109): 1502-3. [PMID:4293850]

4. Fritschy JM, Harvey RJ, Schwarz G. (2008) Gephyrin: where do we stand, where do we go?. Trends Neurosci., 31 (5): 257-64. [PMID:18403029]

5. 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]

6. Grudzinska J, Schemm R, Haeger S, Nicke A, Schmalzing G, Betz H, Laube B. (2005) The beta subunit determines the ligand binding properties of synaptic glycine receptors. Neuron, 45 (5): 727-39. [PMID:15748848]

7. Hilf RJ, Dutzler R. (2008) X-ray structure of a prokaryotic pentameric ligand-gated ion channel. Nature, 452 (7185): 375-9. [PMID:18322461]

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

9. Miyazawa A, Fujiyoshi Y, Unwin N. (2003) Structure and gating mechanism of the acetylcholine receptor pore. Nature, 423 (6943): 949-55. [PMID:12827192]

10. Pfeiffer F, Graham D, Betz H. (1982) Purification by affinity chromatography of the glycine receptor of rat spinal cord. J. Biol. Chem., 257 (16): 9389-93. [PMID:6286620]

11. 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]

12. 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]

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

14. Werman R, Davidoff RA, Aprison MH. (1967) Inhibition of motoneurones by iontophoresis of glycine. Nature, 214 (5089): 681-3. [PMID:4292803]

15. 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]

How to cite this page

To cite this family introduction, please use the following:

Joseph. W. Lynch.
Glycine receptors, introduction. Last modified on 06/03/2014. Accessed on 22/07/2019. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetopharmacology.org/GRAC/FamilyIntroductionForward?familyId=73.