当前位置： SCI文献检索 > NEUROPHARMACOLOGY期刊下所有文献 > The N-terminal domain of the GluN3A subunit determines the efficacy of glycine-activated NMDA receptors.

The N-terminal domain of the GluN3A subunit determines the efficacy of glycine-activated NMDA receptors.

Abstract：

:N-methyl-d-aspartate (NMDA) receptors composed of glycine-binding GluN1 and GluN3 subunits function as excitatory glycine receptors that respond to agonist application only with a very low efficacy. Binding of glycine to the high-affinity GluN3 subunits triggers channel opening, whereas glycine binding to the low-affinity GluN1 subunits causes an auto-inhibition of the maximal glycine-inducible receptor current (Imax). Hence, competitive antagonists of the GluN1 subunit strongly potentiate glycine responses of wild type (wt) GluN1/GluN3 receptors. Here, we show that co-expression of N-terminal domain (NTD) deleted GluN1 (GluN1(ΔNTD)) and GluN3 (GluN3(ΔNTD)) subunits in Xenopus oocytes generates GluN1/GluN3 receptors with a large increase in the glycine-inducible Imax accompanied by a strongly impaired GluN1 antagonist-mediated potentiation. Affinity purification after metabolic or surface labeling revealed no differences in subunit stoichiometry and surface expression between wt GluN1/GluN3A and mutant GluN1(ΔNTD)/GluN3A(ΔNTD) receptors, indicating a specific effect of NTD deletions on the efficacy of receptor opening. Notably, GluN1/GluN3A(ΔNTD) receptors showed a similar increase in Imax and a greatly reduced GluN1 antagonist-mediated current potentiation as GluN1(ΔNTD)/GluN3A(ΔNTD) receptors, whereas the glycine-induced currents of GluN1(ΔNTD)/GluN3A receptors resembled those of wt GluN1/GluN3A receptors. Furthermore, oxidative crosslinking of the homophilic GluN3A NTD intersubunit interface in mutant GluN1/GluN3A(R319C) receptors caused both a decrease in the glycine-induced Imax concomitantly with a marked increase in GluN1 antagonist-mediated current potentiation, whilst mutations within the intrasubunit region linking the GluN3A NTD to the ligand binding domain had opposite effects. Together these results show that the GluN3A NTD constitutes a crucial regulatory determinant of GluN1/GluN3A receptor function.

journal_name

Neuropharmacology

journal_title

Neuropharmacology

authors

Mesic I,Madry C,Geider K,Bernhard M,Betz H,Laube B

doi

10.1016/j.neuropharm.2016.01.014

subject

Has Abstract

pub_date

2016-06-01 00:00:00

pages

133-141

eissn

0028-3908

issn

1873-7064

pii

S0028-3908(16)30014-4

journal_volume

105

pub_type

杂志文章

在线工具

The N-terminal domain of the GluN3A subunit determines the efficacy of glycine-activated NMDA receptors.