Lonotropic glutamate-like receptor δ2 binds D-serine and glycine

The orphan glutamate-like receptor GluR delta 2 is predominantly expressed in Purkinje cells of the central nervous system. The classification of GluR delta 2 to the ionotropic glutamate receptor family is based on sequence similarities, because GluR delta 2 does not form functional homomericglutamate-gated ion channels in transfected cells. Studies in GluR delta 2(-/-) knockout mice as well as in mice with naturally occurring mutations in the GluR delta 2 gene have demonstrated an essential role of GluR delta 2 in cerebellar long-term depression, motor learning, motor coordination, and synaptogenesis. However, the lack of a known agonist has hampered investigations on the function of GluR delta 2. In this study, the ligand-binding core of GluR delta 2 (GluR delta 2-S1S2) was found to bind neutral amino acids such as D-serine and glycine, as demonstrated by isothermal titration calorimetry. Direct evidence for binding Of D-serine and structural rearrangements in the binding cleft of GluR delta 2-S1S2 is provided by x-ray structures of GluR delta 2-S1S2 in its apo form and in complex with D-serine. Functionally, D-serine and glycine were shown to inactivate spontaneous ion-channel conductance in GluR delta 2 containing the lurcher mutation (EC50 values, 182 and 507 mu W, respectively). These data demonstrate that the GluR delta 2 ligand-binding core is capable of binding ligands and that cleft closure of the ligand-binding core can induce conformational changes that alter ion permeation.