Glycine receptor

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Glycine Glycine-2D-skeletal.svg
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 currents. 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]

Contents

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 a2 subunits, while the adult form is made up of both a1 and b subunits. Glycine receptor StructureAgonistsAntagonists.jpg
(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

Related Research Articles

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<span class="mw-page-title-main">Neurotransmitter receptor</span> Type of protein

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An inhibitory postsynaptic potential (IPSP) is a kind of synaptic potential that makes a postsynaptic neuron less likely to generate an action potential. The opposite of an inhibitory postsynaptic potential is an excitatory postsynaptic potential (EPSP), which is a synaptic potential that makes a postsynaptic neuron more likely to generate an action potential. IPSPs can take place at all chemical synapses, which use the secretion of neurotransmitters to create cell-to-cell signalling. EPSPs and IPSPs compete with each other at numerous synapses of a neuron. This determines whether an action potential occurring at the presynaptic terminal produces an action potential at the postsynaptic membrane. Some common neurotransmitters involved in IPSPs are GABA and glycine.

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<span class="mw-page-title-main">GABA receptor</span> Receptors that respond to gamma-aminobutyric acid

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<span class="mw-page-title-main">Ligand-gated ion channel</span> Type of ion channel transmembrane protein

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GABA<sub>A</sub> receptor Ionotropic receptor and ligand-gated ion channel

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<span class="mw-page-title-main">Hyperekplexia</span> Genetic disorder causing an exaggerated startle response

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<span class="mw-page-title-main">Gephyrin</span> Type of protein

Gephyrin is a protein that in humans is encoded by the GPHN gene.

<span class="mw-page-title-main">Chloride potassium symporter 5</span> Protein-coding gene in the species Homo sapiens

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<span class="mw-page-title-main">GLRB</span> Protein-coding gene in the species Homo sapiens

Glycine receptor subunit beta is a protein that in humans is encoded by the GLRB gene.

<span class="mw-page-title-main">GABRD</span> Protein-coding gene in the species Homo sapiens

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<span class="mw-page-title-main">Presynaptic inhibition</span>

Presynaptic inhibition is a phenomenon in which an inhibitory neuron provides synaptic input to the axon of another neuron to make it less likely to fire an action potential. Presynaptic inhibition occurs when an inhibitory neurotransmitter, like GABA, acts on GABA receptors on the axon terminal. Or when endocannabinoids act as retrograde messengers by binding to presynaptic CB1 receptors, thereby indirectly modulating GABA and the excitability of dopamine neurons by reducing it and other presynaptic released neurotransmitters. Presynaptic inhibition is ubiquitous among sensory neurons.

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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