The low binding affinity of D-serine at the ionotropic glutamate receptor GluD2 can be attributed to the hinge region

• Published in: Scientific reports Vol. 7; no. 1; p. 46145
• Main Authors: Tapken, Daniel, Steffensen, Thomas Bielefeldt, Leth, Rasmus, Kristensen, Lise Baadsgaard, Gerbola, Alexander, Gajhede, Michael, Jørgensen, Flemming Steen, Olsen, Lars, Kastrup, Jette Sandholm
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 07.04.2017; Nature Publishing Group
• Subjects: 13; 45/70; 631/337/2265; 631/378/2586; 64; 64/114; 82; 82/16; 82/80; 82/83; 9/74; 96; Affinity; Amino Acid Sequence; Animals; Ataxia; Binding Sites; Calorimetry; Channel gating; D-Serine; Electrophysiology; Glutamic acid receptors (ionotropic); Glycine; Humanities and Social Sciences; Ligands; Molecular Dynamics Simulation; multidisciplinary; Mutant Proteins - chemistry; Mutant Proteins - metabolism; Mutation - genetics; Protein Domains; Rats; Receptors, Glutamate - chemistry; Receptors, Glutamate - metabolism; Receptors, N-Methyl-D-Aspartate - metabolism; Science; Serine - metabolism; Structure-Activity Relationship; Synaptic plasticity; Thermodynamics; Titration; Xenopus
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/srep46145

Ionotropic glutamate receptors (iGluRs) are responsible for most of the fast excitatory communication between neurons in our brain. The GluD2 receptor is a puzzling member of the iGluR family: It is involved in synaptic plasticity, plays a role in human diseases, e.g . ataxia, binds glycine and D-serine with low affinity, yet no ligand has been discovered so far that can activate its ion channel. In this study, we show that the hinge region connecting the two subdomains of the GluD2 ligand-binding domain is responsible for the low affinity of D-serine, by analysing GluD2 mutants with electrophysiology, isothermal titration calorimetry and molecular dynamics calculations. The hinge region is highly variable among iGluRs and fine-tunes gating activity, suggesting that in GluD2 this region has evolved to only respond to micromolar concentrations of D-serine.