Computationally Discovered Potentiating Role of Glycans on NMDA Receptors

TL;DR

This study uses molecular dynamics simulations and electrophysiological experiments to reveal that glycans on NMDA receptors stabilize certain conformations and may enhance receptor activity, providing new insights into glycosylation effects.

Contribution

The paper introduces a computational and experimental approach to demonstrate glycans' potentiating role on NMDA receptor function, which was previously unclear.

Findings

Glycans stabilize closed-clamshell conformations of NMDARs.

Glycans at GluN1-N440 enhance receptor potentiation.

Mutation preventing glycosylation increases EC50 value.

Abstract

N-methyl-D-aspartate receptors (NMDARs) are glycoproteins in the brain central to learning and memory. The effects of glycosylation on the structure and dynamics of NMDARs are largely unknown. In this work, we use extensive molecular dynamics simulations of GluN1 and GluN2B ligand binding domains (LBDs) of NMDARs to investigate these effects. Our simulations predict that intra-domain interactions involving the glycan attached to residue GluN1-N440 stabilize closed-clamshell conformations of the GluN1 LBD. The glycan on GluN2B-N688 shows a similar, though weaker, effect. Based on these results, and assuming the transferability of the results of LBD simulations to the full receptor, we predict that glycans at GluN1-N440 might play a potentiator role in NMDARs. To validate this prediction, we perform electrophysiological analysis of full-length NMDARs with a glycosylation-preventing GluN1-N440Q mutation, and demonstrate an increase in the glycine EC50 value. Overall, our results suggest an intramolecular potentiating role of glycans on NMDA receptors.