Inhibitory glycine receptors: an update

Abstract

Strychnine-sensitive glycine receptors (GlyRs) mediate synaptic inhibition in the spinal cord, brainstem, and other regions of the mammalian central nervous system. In this minireview, we summarize our current view of the structure, ligand-binding sites, and chloride channel of these receptors and discuss recently emerging functions of distinct GlyR isoforms. GlyRs not only regulate the excitability of motor and afferent sensory neurons, including pain fibers, but also are involved in the processing of visual and auditory signals. Hence, GlyRs constitute promising targets for the development of therapeutically useful compounds.

FIGURE 1.

Structures of homomeric α1- and heteromeric α1β-GlyRs modeled using GluCl as a template. Left, α1-GlyR shown with five glycine and ivermectin molecules each and a single picrotoxin molecule bound (ligands depicted as van der Waals spheres). Right, unliganded heteromeric α1β-GlyR with the different interfaces indicated.

FIGURE 2.

Models of the principal (+) and complementary (−) surfaces of the GlyRα1 and GlyRβ agonist-binding regions. In heteromeric GlyRs, the + and − surfaces of the α1 and β subunit ECDs generate non-equivalent agonist-binding sites at the α-β, β-α, or β-β interface, which are all functional. Note the significant sequence divergence (up to eight substitutions) between α1 and β, in particular within loop C.

FIGURE 3.

Transmembrane domains of homo- and heteromeric GlyRs. Left, picrotoxin bound in the chloride channel of the homomeric α1-GlyR. Binding determinants include five Pro-250 and Thr-258 residues each. Right, in the α1β-GlyR, three of the Thr-258 residues are replaced by Phe-282, and three of the Pro-250 residues by Ala-274 of the β subunit. These substitutions explain the ∼50-fold lower affinity of picrotoxin for heteromeric GlyRs.