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TitleAn antidepressant mechanism underlying the allosteric inhibition of GluN2D-incorporated NMDA receptors at GABAergic interneurons.
Journal, issue, pagesSci Adv, Vol. 11, Issue 10, Page eadq0444, Year 2025
Publish dateMar 7, 2025
AuthorsJilin Zhang / Jinjin Duan / Wei Li / Xian Wang / Shimin Ren / Luyu Ye / Fang Liu / Xiaoting Tian / Yang Xie / Yiming Huang / Yidi Sun / Nan Song / Tianyu Li / Xiang Cai / Zhiqiang Liu / Hu Zhou / Chenggang Huang / Yang Li / Shujia Zhu / Fei Guo /
PubMed Abstract-methyl-d-aspartate receptors (NMDARs), key excitatory ion channels, have gained attention as anti-depression targets. NMDARs consist of two GluN1 and two GluN2 subunits (2A-2D), which determine ...-methyl-d-aspartate receptors (NMDARs), key excitatory ion channels, have gained attention as anti-depression targets. NMDARs consist of two GluN1 and two GluN2 subunits (2A-2D), which determine their pharmacological properties. Few compounds selectively targeting GluN2 subunits with antidepressant effects have been identified. Here, we present YY-23, a compound that selectively inhibits GluN2C- or GluN2D-containing NMDARs. Cryo-EM analysis revealed that YY-23 binds to the transmembrane domain of the GluN2D subunit. YY-23 primarily affects GluN2D-containing NMDARs on GABAergic interneurons in the prefrontal cortex, suppressing GABAergic neurotransmission and enhancing excitatory transmission. Behavioral assays demonstrate YY-23's rapid antidepressant effects in both stress-naïve and stress-exposed models, which are lost in mice with global or selective knockout of the gene in parvalbumin-positive interneurons. These findings highlight GluN2D-containing NMDARs on GABAergic interneurons as potential depression treatment targets.
External linksSci Adv / PubMed:40043126 / PubMed Central
MethodsEM (single particle)
Resolution4.2 Å
Structure data

38847

8y1v

EMDB-38847: GluN1b-GluN2D NMDA receptor in complex with competitive antagonist R-CPP and allosteric inhibitor YY-23
PDB-8y1v: Structure of GluN1b-GluN2D NMDA receptor in complex with competitive antagonist R-CPP and allosteric inhibitor YY-23
Method: EM (single particle) / Resolution: 4.2 Å

Chemicals

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose


PDB Unreleased entry

PDB-1lw8: Unknown entry

Source
  • homo sapiens (human)
KeywordsMEMBRANE PROTEIN/INHIBITOR / ion channel / calcium permeable / glutamate receptor / neuronal expression / MEMBRANE PROTEIN / MEMBRANE PROTEIN-INHIBITOR complex

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