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

Peter Naur, Kasper B. Hansen, Anders S. Kristensen, Shashank M. Dravid, Darryl S. Pickering, Lars Olsen, Bente Vestergaard, Jan Egebjerg, Michael Gajhede, Stephen F. Traynelis, Jette S. Kastrup

Research output: Contribution to journalArticle

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Abstract

The orphan glutamate-like receptor GluRδ2 is predominantly expressed in Purkinje cells of the central nervous system. The classification of GluRδ2 to the ionotropic glutamate receptor family is based on sequence similarities, because GluRδ2 does not form functional homomeric glutamate-gated ion channels in transfected cells. Studies in GluRδ2 -/- knockout mice as well as in mice with naturally occurring mutations in the GluRδ2 gene have demonstrated an essential role of GluRδ2 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 GluRδ2. In this study, the ligand-binding core of GluRδ2 (GluRδ2-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 GluRδ2-S1S2 is provided by x-ray structures of GluRδ2-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 GluRδ2 containing the lurcher mutation (EC 50 values, 182 and 507 μM, respectively). These data demonstrate that the GluRδ2 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.

Original languageEnglish
Pages (from-to)14116-14121
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume104
Issue number35
DOIs
StatePublished - Aug 28 2007
Externally publishedYes

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Ionotropic Glutamate Receptors
Glycine
Serine
Ligands
Ion Channels
Neutral Amino Acids
Calorimetry
Mutation
Purkinje Cells
Glutamate Receptors
Knockout Mice
Glutamic Acid
Central Nervous System
X-Rays
Learning
Ions
Depression
Genes

All Science Journal Classification (ASJC) codes

  • Genetics
  • General

Cite this

Ionotropic glutamate-like receptor δ2 binds D-serine and glycine. / Naur, Peter; Hansen, Kasper B.; Kristensen, Anders S.; Dravid, Shashank M.; Pickering, Darryl S.; Olsen, Lars; Vestergaard, Bente; Egebjerg, Jan; Gajhede, Michael; Traynelis, Stephen F.; Kastrup, Jette S.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 104, No. 35, 28.08.2007, p. 14116-14121.

Research output: Contribution to journalArticle

Naur, P, Hansen, KB, Kristensen, AS, Dravid, SM, Pickering, DS, Olsen, L, Vestergaard, B, Egebjerg, J, Gajhede, M, Traynelis, SF & Kastrup, JS 2007, 'Ionotropic glutamate-like receptor δ2 binds D-serine and glycine', Proceedings of the National Academy of Sciences of the United States of America, vol. 104, no. 35, pp. 14116-14121. https://doi.org/10.1073/pnas.0703718104
Naur, Peter ; Hansen, Kasper B. ; Kristensen, Anders S. ; Dravid, Shashank M. ; Pickering, Darryl S. ; Olsen, Lars ; Vestergaard, Bente ; Egebjerg, Jan ; Gajhede, Michael ; Traynelis, Stephen F. ; Kastrup, Jette S. / Ionotropic glutamate-like receptor δ2 binds D-serine and glycine. In: Proceedings of the National Academy of Sciences of the United States of America. 2007 ; Vol. 104, No. 35. pp. 14116-14121.
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