Glycine receptor

The glycine receptor, or GlyR, is the receptor for 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 brain stem.[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 has recently been found to also be a competitive antagonist.[3]

Contents

Arrangement of subunits

Strychnine-sensitive glycine receptors 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.[4]

There are presently four known isoforms of the α-subunit (α1-4) of GlyR that are essential to bind ligands (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 [5] or four α1 subunits and one β subunit.[6] The α-subunits are also able to form functional homo-pentameric receptors in heterologous expression systems in African clawed frog's oocytes or mammalian cell lines,[6] and the α1 homomeric receptor is essential for studies of channel pharmacokinetics and pharmacodynamics.[7]

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.[8]

Research

Quantum dots have been used to track the diffusion of glycine receptors into the synapse of neurons.[9]

Formation of the mature GlyR complex at the post-synaptic membrane was found to be reliant on presence of a protein called gephyrin, via knockout studies in mice.[10]

Ligands

Agonists

Antagonists

References

  1. ^ a b Lynch JW (October 2004). "Molecular structure and function of the glycine receptor chloride channel". Physiological reviews 84 (4): 1051–95. doi:10.1152/physrev.00042.2003. PMID 15383648. 
  2. ^ Rajendra, S; Lynch JW, Schofield PR (1997). "The glycine receptor". Pharmacology and Therapeutics 73 (2): 121–146. doi:10.1016/S0163-7258(96)00163-5. PMID 9131721. 
  3. ^ Duan L, Yang J, Slaughter MM. (2009). Caffeine inhibition of ionotropic glycine receptors. J Physiol. 587(Pt 16):4063-75. doi:10.1113/jphysiol.2009.174797 PMID 19564396
  4. ^ Miyazawa, A; Fujiyoshi Y, Unwin N (2003). "Structure and gating mechanism of the acetylcholine receptor pore". Nature 423 (6943): 949–955. doi:10.1038/nature01748. PMID 12827192. 
  5. ^ Kuhse, J; Laube B, Magalei D, Betz H (1993). "Assembly of the inhibitory glycine receptor: identification of amino acid sequence motifs governing subunit stoichiometry". Neuron 11 (6): 1049–1056. doi:10.1016/0896-6273(93)90218-G. PMID 8274276. 
  6. ^ a b Kuhse, J; Betz H, Kirsch J (1995). "The inhibitory glycine receptor: architecture, synaptic localization and molecular pathology of a postsynaptic ion-channel complex". Current Opinion in Neurobiology 5 (3): 318–323. doi:10.1016/0959-4388(95)80044-1. PMID 7580154. 
  7. ^ Lewis, TM; Schofield PR, McClellan AM (2003). "Kinetic determinants of agonist action at the recombinant human glycine receptor". Journal of Physiology 549 (Part 2): 361–374. doi:10.1113/jphysiol.2002.037796. PMC 2342959. PMID 12679369. http://jp.physoc.org/cgi/content/full/549/2/361. Retrieved 2007-01-16. 
  8. ^ Online 'Mendelian Inheritance in Man' (OMIM) STIFF-PERSON SYNDROME; SPS -184850
  9. ^ Dahan M, Lévi S, Luccardini C, Rostaing P, Riveau B, Triller A (2003). "Diffusion dynamics of glycine receptors revealed by single-quantum dot tracking". Science 302 (5644): 442–5. Bibcode 2003Sci...302..442D. doi:10.1126/science.1088525. PMID 14564008. 
  10. ^ Feng G, Tintrup H, Kirsch J, et al. (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. 

External links

Cys-loop receptors
5-HT3 (A, B, C, D, E)
GABAA (α1, α2, α3, α4, α5, α6, β1, β2, β3, γ1, γ2, γ3, δ, ε, π, θ) · GABAA-ρ (ρ1, ρ2, ρ3)
Glycine
α1 · α2 · α3 · α4 · β
monomers: α1 · α2 · α3 · α4 · α5 · α6 · α7 · α9 · α10 · β1 · β2 · β3 · β4 · δ · ε
pentamers: (α3)2(β4)3 · (α4)2(β2)3 · (α7)5 · (α1)2(β4)3 - Ganglion type · (α1)2β1δε - Muscle type
Zinc
Ionotropic glutamates
Ligand-gated only
AMPA (1, 2, 3, 4) · Kainate (1, 2, 3, 4, 5)
Voltage- and ligand-gated
NMDA (1, 2A, 2B, 2C, 2D, 3A, 3B, L1A, L1B)
‘Orphan’
GluD (δ1, δ2)
ATP-gated channels
P2X (1, 2, 3, 4, 5, 6, 7)
B trdu: iter (nrpl/grfl/cytl/horl), csrc (lgic, enzr, gprc, igsr, intg, nrpr/grfr/cytr), itra (adap, gbpr, mapk), calc, lipd; path (hedp, wntp, tgfp+mapp, notp, jakp, fsap, hipp, tlrp)