Glycine

The glycine receptor (abbreviated as GlyR or GLR) is the receptor of the amino acid neurotransmitter glycine. GlyR is an ionotropic receptor that produces its effects through chloride current. It is one of the most widely distributed inhibitory receptors in the central nervous system and has important roles in a variety of physiological processes, especially in mediating inhibitory neurotransmission in the spinal cord and brainstem.[1]

The receptor can be activated by a range of simple amino acids including glycine, β-alanine and taurine, and can be selectively blocked by the high-affinity competitive antagonist strychnine.[2] Caffeine is a competitive antagonist of GlyR.[3] Cannabinoids enhance the function.[4]

The protein Gephyrin has been shown to be necessary for GlyR clustering at inhibitory synapses.[5][6] GlyR is known to colocalize with the GABAA receptor on some hippocampal neurons.[5] Nevertheless, some exceptions can occur in the central nervous system where the GlyR α1 subunit and gephyrin, its anchoring protein, are not found in dorsal root ganglion neurons despite the presence of GABAA receptors.[7]

History

Glycine and its receptor were first suggested to play a role in inhibition of cells in 1965.[8] Two years later, experiments showed that glycine had a hyperpolarizing effect on spinal motor neurons[9] due to increased chloride conductance through the receptor.[10] Then, in 1971, glycine was found to be localized in the spinal cord using autoradiography.[11] All of these discoveries resulted in the conclusion that glycine is a primary inhibitory neurotransmitter of the spinal cord that works via its receptor.

Arrangement of subunits

(a): shows three agonists and one antagonist of the glycine receptor. (b): the fetal form of the receptor is made up of five α2 subunits, while the adult form is made up of both α1 and β subunits.

Strychnine-sensitive GlyRs are members of a family of ligand-gated ion channels. Receptors of this family are arranged as five subunits surrounding a central pore, with each subunit composed of four α helical transmembrane segments.[12] There are presently four known isoforms of the ligand-binding α-subunit (α1-4) of GlyR (GLRA1, GLRA2, GLRA3, GLRA4) and a single β-subunit (GLRB). The adult form of the GlyR is the heteromeric α1β receptor, which is believed to have a stoichiometry (proportion) of three α1 subunits and two β subunits[13] or four α1 subunits and one β subunit.[14] The embryo form on the other hand, is made up of five α2 subunits.[15] The α-subunits are also able to form functional homopentamers in heterologous expression systems in African clawed frog oocytes or mammalian cell lines, which are useful for studies of channel pharmacokinetics and pharmacodynamics.[14] The β subunit is unable to form functional channels without α subunits but determines the synaptic localization of GlyRs and the pharmacological profile of glycinergic currents.[16]

Function

Adults

In mature adults, glycine is a inhibitory neurotransmitter found in the spinal cord and regions of the brain.[15] As it binds to a glycine receptor, a conformational change is induced, and the channel created by the receptor opens.[17] As the channel opens, chloride ions are able to flow into the cell which results in hyperpolarization. In addition to this hyperpolarization, which decreases the likelihood of action potential propagation, glycine is also responsible for decreasing the release of both inhibitory and excitatory neurotransmitters as it binds to its receptor.[18] This is called the "shunting" effect and can be explained by Ohm's Law. As the receptor is activated, the membrane conductance is increased and the membrane resistance is decreased. According to Ohm's Law, as resistance decreases, so does voltage. A decreased postsynaptic voltage results in a decreased release of neurotransmitters.[18]

Embryos

In developing embryos, glycine has the opposite effect as it does in adults. It is an excitatory neurotransmitter.[18] This is due to the fact that chloride has a more positive equilibrium potential in early stages of life due to the high expression of NKCC1. This moves one sodium, one potassium and two chloride ions into the cell, resulting in a higher intracellular chloride concentration. When glycine binds to its receptor, the result is an efflux of chloride, instead of an influx as it happens in mature adults. The efflux of chloride causes the membrane potential to become more positive, or depolarized. As the cells mature, the K+-Cl- cotransporter 2 (KCC2) is expressed, which moves potassium and chloride out of the cell, decreasing the intracellular chloride concentration. This allows the receptor to switch to an inhibitory mechanism as described above for adults.[18]

Glycine receptors in diseases

Disruption of GlyR surface expression or reduced ability of expressed GlyRs to conduct chloride ions results in the rare neurological disorder, hyperekplexia. The disorder is characterized by an exaggerated response to unexpected stimuli which is followed by a temporary but complete muscular rigidity often resulting in an unprotected fall. Chronic injuries as a result of the falls are symptomatic of the disorder.[1] A mutation in GLRA1 is responsible for some cases of stiff person syndrome.[19]

Ligands

Agonists

Positive Allosteric Modulators

Antagonists

References

  1. 1 2 Lynch JW (October 2004). "Molecular structure and function of the glycine receptor chloride channel". Physiological Reviews. 84 (4): 1051–95. CiteSeerX 10.1.1.326.8827. doi:10.1152/physrev.00042.2003. PMID 15383648.
  2. ↑ Rajendra S, Lynch JW, Schofield PR (1997). "The glycine receptor". Pharmacology & Therapeutics. 73 (2): 121–146. doi:10.1016/S0163-7258(96)00163-5. PMID 9131721.
  3. ↑ Duan L, Yang J, Slaughter MM (August 2009). "Caffeine inhibition of ionotropic glycine receptors". The Journal of Physiology. 587 (Pt 16): 4063–75. doi:10.1113/jphysiol.2009.174797. PMC 2756438. PMID 19564396.
  4. ↑ Xiong, Wei (2011). "Cannabinoid potentiation of glycine receptors contributes to cannabis-induced analgesia". Nature Chemical Biology. 7 (5): 296–303. doi:10.1038/nchembio.552. PMC 3388539. PMID 21460829.
  5. 1 2 Lévi S, Logan SM, Tovar KR, Craig AM (January 2004). "Gephyrin is critical for glycine receptor clustering but not for the formation of functional GABAergic synapses in hippocampal neurons". The Journal of Neuroscience. 24 (1): 207–17. doi:10.1523/JNEUROSCI.1661-03.2004. PMC 6729579. PMID 14715953.
  6. ↑ Feng G, Tintrup H, Kirsch J, Nichol MC, Kuhse J, Betz H, Sanes JR (November 1998). "Dual requirement for gephyrin in glycine receptor clustering and molybdoenzyme activity". Science. 282 (5392): 1321–4. Bibcode:1998Sci...282.1321F. doi:10.1126/science.282.5392.1321. PMID 9812897.
  7. ↑ Lorenzo LE, Godin AG, Wang F, St-Louis M, Carbonetto S, Wiseman PW, et al. (June 2014). "Gephyrin clusters are absent from small diameter primary afferent terminals despite the presence of GABA(A) receptors". The Journal of Neuroscience. 34 (24): 8300–17. doi:10.1523/JNEUROSCI.0159-14.2014. PMC 6608243. PMID 24920633.
  8. ↑ Aprison, M.H.; Werman, R. (November 1965). "The distribution of glycine in cat spinal cord and roots". Life Sciences. 4 (21): 2075–2083. doi:10.1016/0024-3205(65)90325-5. PMID 5866625.
  9. ↑ Werman, R.; Davidoff, R. A.; Aprison, M. H. (May 1967). "Is Glycine a Neurotransmitter ?: Inhibition of Motoneurones by Iontophoresis of Glycine". Nature. 214 (5089): 681–683. Bibcode:1967Natur.214..681W. doi:10.1038/214681a0. ISSN 0028-0836. PMID 4292803. S2CID 4198837.
  10. ↑ Werman, R; Davidoff, R A; Aprison, M H (January 1968). "Inhibitory of glycine on spinal neurons in the cat". Journal of Neurophysiology. 31 (1): 81–95. doi:10.1152/jn.1968.31.1.81. ISSN 0022-3077. PMID 4384497.
  11. ↑ Hökfelt, Tomas; Ljungdahl, Åke (September 1971). "Light and electron microscopic autoradiography on spinal cord slices after incubation with labeled glycine". Brain Research. 32 (1): 189–194. doi:10.1016/0006-8993(71)90163-6. PMID 4329648.
  12. ↑ Miyazawa A, Fujiyoshi Y, Unwin N (June 2003). "Structure and gating mechanism of the acetylcholine receptor pore". Nature. 423 (6943): 949–55. Bibcode:2003Natur.423..949M. doi:10.1038/nature01748. PMID 12827192. S2CID 205209809.
  13. ↑ Kuhse J, Laube B, Magalei D, Betz H (December 1993). "Assembly of the inhibitory glycine receptor: identification of amino acid sequence motifs governing subunit stoichiometry". Neuron. 11 (6): 1049–56. doi:10.1016/0896-6273(93)90218-G. PMID 8274276. S2CID 25411536.
  14. 1 2 Kuhse J, Betz H, Kirsch J (June 1995). "The inhibitory glycine receptor: architecture, synaptic localization and molecular pathology of a postsynaptic ion-channel complex". Current Opinion in Neurobiology. 5 (3): 318–23. doi:10.1016/0959-4388(95)80044-1. PMID 7580154. S2CID 42056647.
  15. 1 2 Rajendra, Sundran; Lynch, Joseph W.; Schofield, Peter R. (January 1997). "The glycine receptor". Pharmacology & Therapeutics. 73 (2): 121–146. doi:10.1016/S0163-7258(96)00163-5. PMID 9131721.
  16. ↑ Galaz P, Barra R, Figueroa H, Mariqueo T (Aug 2015). "Advances in the pharmacology of LGICs auxiliary subunits" (PDF). Pharmacol. Res. 101 (101): 65–73. doi:10.1016/j.phrs.2015.07.026. PMID 26255765.
  17. ↑ Breitinger, Hans-Georg; Becker, Cord-Michael (2002). "The Inhibitory Glycine Receptor—Simple Views of a Complicated Channel". ChemBioChem. 3 (11): 1042–1052. doi:10.1002/1439-7633(20021104)3:11<1042::AID-CBIC1042>3.0.CO;2-7. ISSN 1439-7633. PMID 12404628. S2CID 41022948.
  18. 1 2 3 4 Xu, Tian-Le; Gong, Neng (August 2010). "Glycine and glycine receptor signaling in hippocampal neurons: Diversity, function and regulation". Progress in Neurobiology. 91 (4): 349–361. doi:10.1016/j.pneurobio.2010.04.008. PMID 20438799. S2CID 247871.
  19. ↑ Online Mendelian Inheritance in Man (OMIM): STIFF-PERSON SYNDROME; SPS - 184850
  20. ↑ Shan Q, Haddrill JL, Lynch JW (April 2001). "Ivermectin, an unconventional agonist of the glycine receptor chloride channel". The Journal of Biological Chemistry. 276 (16): 12556–64. doi:10.1074/jbc.M011264200. PMID 11278873.
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