| Description: |
Neurotransmitter ligand-gated ion channels are transmembrane receptor-ion channel complexes that open transiently upon binding of specific ligands, allowing rapid transmission of signals at chemical synapses [, ]. Five of these ion channel receptor families have been shown to form a sequence-related superfamily:Nicotinic acetylcholine receptor (AchR), an excitatory cation channel in vertebrates and invertebrates; in vertebrate motor endplates it is composed of alpha, beta, gamma and delta/epsilon subunits; in neurons it is composed of alpha and non-alpha (or beta) subunits [].Glycine receptor, an inhibitory chloride ion channel composed of alpha and beta subunits [].Gamma-aminobutyric acid (GABA) receptor, an inhibitory chloride ion channel; at least four types of subunits (alpha, beta, gamma and delta) are known [].Serotonin 5HT3 receptor, of which there are seven major types (5HT3-5HT7) [].Glutamate receptor, an excitatory cation channel of which at least three types have been described (kainate, N-methyl-D-aspartate (NMDA) and quisqualate) [].These receptors possess a pentameric structure (made up of varying subunits), surrounding a central pore. All known sequences of subunits from neurotransmitter-gated ion-channels are structurally related. They are composed of a large extracellular glycosylated N-terminal ligand-binding domain, followed by three hydrophobic transmembrane regions which form the ionic channel, followed by an intracellular region of variable length. A fourth hydrophobic region is found at the C-terminal of the sequence [, ].Glycine is a major inhibitory neurotransmitter (NT) in the adult vertebratecentral nervous system (CNS). Glycinergic synapses have a well-establishedrole in the processing of motor and sensory information that controlsmovement, vision and audition []. This action of glycine is mediatedthrough its interaction with the glycine receptor (GlyR): an intrinsicchloride channel is opened in response to agonist binding. The subsequentinflux of anions prevents membrane depolarisation and neuronal firinginduced by excitatory NTs. Strychnine acts as a competitive antagonist ofglycine binding, thereby reducing the activity of inhibitory neurones.Poisoning with strychnine is characterised by over-excitation, muscle spasmsand convulsions. Whilst glycine is the principal physiological agonist atGlyRs, taurine and beta-alanine also behave as agonists []. Compounds thatmodulate GlyR activity include zinc, some alcohols and anaesthetics,picrotoxin, cocaine and some anticonvulsants. GlyRs were thought for sometime to be localised exclusively in the brain stem and spinal cord, but havesince been found to be expressed more widely, including the cochlear nuclei,cerebellar cortex and forebrain [].GlyRs belong to the ligand-gated ion channel family, which also includes theinhibitory gamma-aminobutyric acid type A (GABAA) and excitatory nicotinicacetylcholine (nACh) and serotonin type 3 (5-HT3) receptors [].Affinity-purified GlyR was found to contain two glycosylated membraneproteins of 48kDa and 56kDa, corresponding to alpha and beta subunits,respectively. Four genes encoding alpha subunits have been identified (GLRA1to 4), together with a single beta polypeptide (GLRB). The heterogeneity ofalpha subunits is further increased by alternative exon splicing, yieldingtwo isoforms of GLRA1 to 3 []. The characteristics of different GlyRsubtypes, therefore, can be largely explained by their GLRA content.GlyRs are generally believed to adopt a pentameric structure in vivo: fivesubunits assemble to form a ring structure with a central pore. Typically, astoichiometry of 3:2 (alpha:beta) is observed []. GlyR subunits share ahigh overall level of sequence similarity both with themselves and with thesubunits of the GABAA and nACh receptors. Four highly conserved segmentshave been proposed to correspond to transmembrane (TM) alpha helices (TM1-4), the second of which is thought to contribute to the pore wall []. A long extracellular N-terminal segment precedes TM1 and a long cytoplasmic loop links TM3 and 4. Short cytoplasmic and extracellular loops join TM1-2 andTM2-3, respectively, and a short C-terminal sequence follows TM4. Studiesusing radiolabelled strychnine have shown the alpha subunit to beresponsible for ligand binding, the critical residues for this interaction lying within the N-terminal domain. The beta subunit plays a structuralrole, contributing one of its TM domains to the pore wall as well as playinga putative role in postsynaptic clustering of the receptor.In several mammalian species, defects in glycinergic transmission areassociated with complex motor disorders. Mutations in the gene encodingGLRA1 give rise to hyperplexia, or startle disease []. This ischaracterised by muscular spasms in response to unexpected light or noisestimuli, similar to the symptoms of sublethal doses of strychnine. Themutations result in amino acid substitutions within the TM1-2 and TM3-4loops, suggesting that these regions are involved in the transduction ofligand binding into channel activation.GLRA3 is expressed in thecerebellum, olfactory bulb and hippocampus. GLRA3 trancripts, together withGLRA1, predominate in the postnatal CNS, replacing GLRA2, which is moreabundant in embryonic and neonatal neurones. |
