Glycine receptor alpha (Glycine_rcpt_A)
Type: Family

Glycine is a major inhibitory neurotransmitter (NT) in the adult vertebrate central nervous system (CNS). Glycinergic synapses have a well-established role in the processing of motor and sensory information that controls movement, vision and audition . This action of glycine is mediated through its interaction with the glycine receptor (GlyR): an intrinsic chloride channel is opened in response to agonist binding. The subsequent influx of anions prevents membrane depolarisation and neuronal firing induced by excitatory NTs. Strychnine acts as a competitive antagonist of glycine binding, thereby reducing the activity of inhibitory neurones. Poisoning with strychnine is characterised by over-excitation, muscle spasms and convulsions. Whilst glycine is the principal physiological agonist at GlyRs, taurine and beta-alanine also behave as agonists . Compounds that modulate GlyR activity include zinc, some alcohols and anaesthetics, picrotoxin, cocaine and some anticonvulsants. GlyRs were thought for some time to be localised exclusively in the brain stem and spinal cord, but have since 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 the inhibitory gamma-aminobutyric acid type A (GABAA) and excitatory nicotinic acetylcholine (nACh) and serotonin type 3 (5-HT3) receptors . Affinity-purified GlyR was found to contain two glycosylated membrane proteins of 48kDa and 56kDa, corresponding to alpha and beta subunits, respectively. Four genes encoding alpha subunits have been identified (GLRA1 to 4), together with a single beta polypeptide (GLRB). The heterogeneity of alpha subunits is further increased by alternative exon splicing, yielding two isoforms of GLRA1 to 3 . The characteristics of different GlyR subtypes, therefore, can be largely explained by their GLRA content.

GlyRs are generally believed to adopt a pentameric structure in vivo: five subunits assemble to form a ring structure with a central pore. Typically, a stoichiometry of 3:2 (alpha:beta) is observed . GlyR subunits share a high overall level of sequence similarity both with themselves and with the subunits of the GABAA and nACh receptors. Four highly conserved segments have been proposed to correspond to transmembrane (TM) α-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 and TM2-3, respectively, and a short C-terminal sequence follows TM4. Studies using radiolabelled strychnine have shown the alpha subunit to be responsible for ligand binding, the critical residues for this interaction lying within the N-terminal domain. The beta subunit plays a structural role, contributing one of its TM domains to the pore wall as well as playing a putative role in postsynaptic clustering of the receptor.

In several mammalian species, defects in glycinergic transmission are associated with complex motor disorders. Mutations in the gene encoding GLRA1 give rise to hyperplexia, or startle disease . This is characterised by muscular spasms in response to unexpected light or noise stimuli, similar to the symptoms of sublethal doses of strychnine. The mutations result in amino acid substitutions within the TM1-2 and TM3-4 loops, suggesting that these regions are involved in the transduction of ligand binding into channel activation.