The glycine receptor is a member of the Cys-loop superfamily of transmitter-gated ion channels ^[1]. 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 ^[2].

Receptors of this family are arranged as five subunits surrounding a central pore, with each subunit composed of four α helical transmembrane segments ^[3]. 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^[4] or four α1 subunits and one β subunit ^[5].

In the glycine receptor, antagonist (strychnine) binding requires an interaction with residues Lys-200 and Tyr-202 (red sphere in the 3D structure viewer) ^[5]. Strychnine inhibits GlyR by binding to glycine-binding site ^[6].

The zinc ion (Zn²⁺) and proton (H⁺) are critical regulators for the glycine receptor chloride channel in physiological and pathological conditions. Both ions bind to the H109 residue at the extracellular agonist binding domain. H109A, and use the inhibitory potencies of six structurally-diverse channel pore blockers (niflumic acid, picrotoxin, bilobalide, ginkgolide A, ginkgolide B and ginkgolide C) with various molecular volumes to measure the H109A mutation's effect on channel pore conformation. We found that their inhibitory potencies were mostly reduced by the H109A mutation and the extents of reduction were positively correlated with the molecular volumes of the blockers ^[6]. chloride channel of the recombinant alpha 1-subunit homooligomeric glycine receptor is efficiently blocked by cyanotriphenylborate (CTB) with a concentration effecting 50% inhibition (IC₅₀) of 1.3 microM in the presence of 50 microM glycine, and a single glycine residue at position 254 of the alpha 1 subunit is critical for CTB sensitivity ^[6].

Agonist-binding site of this receptor is located at the residue Thr-204. The agonist binding site interaction is thus likely to be mediated by hydrogen bonding and not by ionic interactions ^[5]. The extent of binding pocket contraction, however, is different between full and partial agonists, with the volume of the agonist binding pocket smallest in the glycine-bound structure ^[6]. Thr220 in loop C, Phe175 in loop B, Arg81 in β2, and Ser145 in β6 all coordinate taurine and GABA in a manner that is similar, yet slightly different than their coordination of glycine ^[6]. Besides, an interaction of the glycine agonist with S129 (black sphere in the 3D structure viewer) and E211 ^[6].

A lysine to proline mutation was introduced into the TM2-TM3 linker region at position 281 (K281P) of the alpha1 GlyR. Mutation at this residue did not affect thiol binding to residues in TM2 or TM3 and it does not appear that residue 281 constitutes part of the alcohol binding site. The K281P receptors displayed constitutive activity in the absence of glycine, and unlike wild-type receptors, this channel opening was antagonized by application of either volatile anesthetics or another GlyR modulator, zinc ^[7]. Phosphorylation of S346 was found to induce conformational changes not only at the external end of M2, but also in the glycine-binding site ^[7].