Excitatory and inhibitory D-serine binding to the NMDA receptor

Abstract

N-methyl-D-aspartate receptors (NMDARs) uniquely require binding of two different neurotransmitter agonists for synaptic transmission. D-serine and glycine bind to one subunit, GluN1, while glutamate binds to the other, GluN2. These agonists bind to the receptor’s bi-lobed ligand-binding domains (LBDs), which close around the agonist during receptor activation. To better understand the unexplored mechanisms by which D-serine contributes to receptor activation, we performed multi-microsecond molecular dynamics simulations of the GluN1/GluN2A LBD dimer with free D-serine and glutamate agonists. Surprisingly, we observed D-serine binding to both GluN1 and GluN2A LBDs, suggesting that D-serine competes with glutamate for binding to GluN2A. This mechanism is confirmed by our electrophysiology experiments, which show that D-serine is indeed inhibitory at high concentrations. Although free energy calculations indicate that D-serine stabilizes the closed GluN2A LBD, its inhibitory behavior suggests that it either does not remain bound long enough or does not generate sufficient force for ion channel gating. We developed a workflow using pathway similarity analysis to identify groups of residues working together to promote binding. These conformation-dependent pathways were not significantly impacted by the presence of N-linked glycans, which act primarily by interacting with the LBD bottom lobe to stabilize the closed LBD.

Nutritional Modulation of Sleep Latency, Duration, and Efficiency: A Randomized, Repeated-Measures, Double-Blind Deception Study

“…L-glutamic acid has been highlighted as a potent excitatory neurotransmitter, resulting in the stimulation of the orexinergic neurons, which in turn promotes arousal and inhibition of both non-rapid eye and rapid eye movement sleep stages (46). Conversely, both endogenous melatonin and D-serine have been demonstrated to attenuate the excitatory neurotransmitter action of L-glutamic acid via inhibition of specific NMDA receptor binding sites (47,48). To that end, it is tempting to speculate that the upregulated metabolomic abundance of urinary 6-sulfatoxymelatonin and D-serine in the intervention trial may have resulted in the downregulated metabolomic abundance of L-glutamic acid, therefore leading to greater subjective and objective sleep enhancement in comparison with the placebo trial.…”