Modulation of Recombinant Human α1 Glycine Receptors by Mono- and Disaccharides: A Kinetic Study

Glycine receptors (GlyRs) mediate fast synaptic inhibition in spinal cord, brainstem, and higher brain centers. Recently, glucose was identified as a positive modulator of GlyR-mediated currents. Here, we investigated extent and kinetics of the positive modulation of recombinant human α1 glycine receptors by different mono- and disaccharides and sorbitol using patch-clamp recording techniques. Glucose and fructose augmented glycine-mediated whole-cell currents with an EC50 of 6-7 mM. At concentrations > 10 mM, the maximum of current enhancement was reached within ∼30 min. Kinetics of GlyR modulation resemble those of protein glycation. On-rates were <0.5 h for saturating concentrations of monosaccharides and ∼1.5 h for disaccharides. Off-rates were considerably slower (>24 h). Galactose, the C4-epimer of glucose, and the sugar alcohol sorbitol had no effect on GlyR currents. Recent cryoelectron microscopy structures were used to identify a potential binding site for saccharides near the ivermectin binding pocket with lysine 143 as possible attachment site. The GlyR mutant α1(K143A) was not potentiated by glucose, suggesting an involvement of this residue in glycine receptor modulation by saccharides.