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

Daniel Tapken; Thomas Bielefeldt Steffensen; Rasmus Leth; Lise Baadsgaard Kristensen; Alexander Gerbola; Michael Gajhede; Flemming Steen Jørgensen; Lars Olsen; Jette Sandholm Kastrup

doi:10.1038/srep46145

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

Daniel Tapken, Thomas Bielefeldt Steffensen, Rasmus Leth, Lise Baadsgaard Kristensen, Alexander Gerbola, Michael Gajhede, Flemming Steen Jørgensen, Lars Olsen, Jette Sandholm Kastrup

8 Citationer (Scopus)

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Abstract

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.

Originalsprog	Engelsk
Artikelnummer	46145
Tidsskrift	Scientific Reports
Vol/bind	7
Antal sider	12
ISSN	2045-2322
DOI	https://doi.org/10.1038/srep46145
Status	Udgivet - 7 apr. 2017

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abstract = "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.",

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T1 - The low binding affinity of D-serine at the ionotropic glutamate receptor GluD2 can be attributed to the hinge region

AU - Tapken, Daniel

AU - Steffensen, Thomas Bielefeldt

AU - Leth, Rasmus

AU - Kristensen, Lise Baadsgaard

AU - Gerbola, Alexander

AU - Gajhede, Michael

AU - Jørgensen, Flemming Steen

AU - Olsen, Lars

AU - Kastrup, Jette Sandholm

PY - 2017/4/7

Y1 - 2017/4/7

N2 - 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.

AB - 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.

KW - Journal Article

U2 - 10.1038/srep46145

DO - 10.1038/srep46145

M3 - Journal article

C2 - 28387240

SN - 2045-2322

VL - 7

JO - Scientific Reports

JF - Scientific Reports

M1 - 46145

ER -

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

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