Abstract
GluN3A and GluN3B are glycine-binding subunits belonging to the NMDA receptor (NMDAR) family that can assemble with the GluN1 subunit to form unconventional receptors activated by glycine alone. Functional characterization of GluN1/GluN3 NMDARs has been difficult. Here, we uncover two modalities that have transformative properties on GluN1/GluN3A receptors. First, we identify a compound, CGP-78608, which greatly enhances GluN1/GluN3A responses, converting small and rapidly desensitizing currents into large and stable responses. Second, we show that an endogenous GluN3A disulfide bond endows GluN1/GluN3A receptors with distinct redox modulation, profoundly affecting agonist sensitivity and gating kinetics. Under reducing conditions, ambient glycine is sufficient to generate tonic receptor activation. Finally, using CGP-78608 on P8-P12 mouse hippocampal slices, we demonstrate that excitatory glycine GluN1/GluN3A NMDARs are functionally expressed in native neurons, at least in the juvenile brain. Our work opens new perspectives on the exploration of excitatory glycine receptors in brain function and development.
Highlights
GluN3A and GluN3B are glycine-binding subunits belonging to the NMDA receptor (NMDAR) family that can assemble with the GluN1 subunit to form unconventional receptors activated by glycine alone
We expressed diheteromeric GluN1/GluN3A receptors in HEK293 cells and studied their activity using whole-cell patch-clamp recordings coupled to a fast perfusion system
Introduction of the GluN1-F484A mutation to prevent ligand binding to the GluN1 subunit[23,24] almost completely abolished the potentiating effects of CGP-78608 (Fig. 1d and Supplementary Figure 1b), consistent with CGP-78608 binding to GluN1 ABDs of GluN1/GluN3 receptors as it does on conventional GluN1/GluN2 receptors
Summary
GluN3A and GluN3B are glycine-binding subunits belonging to the NMDA receptor (NMDAR) family that can assemble with the GluN1 subunit to form unconventional receptors activated by glycine alone. Unconventional glycine-activated GluN1/GluN3 NMDARs have sparked intense curiosity and controversy They constitute a new type of glycine excitatory receptor, since glycine is well established as an inhibitory neurotransmitter in the spinal cord and brainstem[25,26,27]. The effects produced are unprecedented in their extent with potentiation factors much greater than previously observed with other GluN1-binding molecules Building on this discovery, we show that GluN1/GluN3A receptors can alternate between two modes of agonist sensitivity in a redox-dependent manner. This work has broad ranging implications for the study of GluN1/GluN3A receptors and of glycine as an excitatory neurotransmitter
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