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Triheteromeric NMDA receptors: from structure to synaptic physiology.

ABSTRACT: N-methyl-D-aspartate receptors (NMDARs) are glutamate-gated ion channels that play crucial roles in brain development and synaptic plasticity. They are also therapeutic targets of interest since their dysfunction is associated with multiple neurological and psychiatric disorders. In vivo, NMDARs exist as multiple subtypes that differ in their subunit composition, anatomical distribution, functional properties, as well as signaling capacities. While much is known about diheteromeric NMDARs composed of two GluN1 subunits and two identical GluN2 (or GluN3) subunits, the majority of native NMDARs are triheteromers containing two GluN1 and two different GluN2 (or a combination of GluN2 and GluN3). Knowledge about triheteromeric NMDARs has recently boomed, with the first decoding of their atomic structure and the development of a new methodology allowing selective expression of recombinant triheteromers at the cell-surface without confounding co-expression of diheteromers. Here we review these progresses and highlight the unique attributes of triheteromers. Particular emphasis is put on GluN1/GluN2A/GluN2B triheteromers, presumably the most abundant NMDARs in the adult forebrain and critical actors of synaptic plasticity. Better understanding triheteromeric NMDAR structure and function is of major interest for brain physiology and drug discovery.

SUBMITTER: Stroebel D

PROVIDER: S-EPMC5905667 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature

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Triheteromeric NMDA receptors: from structure to synaptic physiology.

Stroebel David D Casado Mariano M Paoletti Pierre P

Current opinion in physiology 20171219

N-methyl-D-aspartate receptors (NMDARs) are glutamate-gated ion channels that play crucial roles in brain development and synaptic plasticity. They are also therapeutic targets of interest since their dysfunction is associated with multiple neurological and psychiatric disorders. <i>In vivo</i>, NMDARs exist as multiple subtypes that differ in their subunit composition, anatomical distribution, functional properties, as well as signaling capacities. While much is known about diheteromeric NMDARs ...[more]

PMID: 29682629

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Project description:Key pointsTriheteromeric NMDA receptors contain two GluN1 and two distinct GluN2 subunits and mediate excitatory neurotransmission in the CNS. Triheteromeric GluN1/2B/2D receptors have functional properties intermediate to those of diheteromeric GluN1/2B and GluN1/2D receptors. GluN1/2B/2D receptors are more sensitive to channel blockade by ketamine and memantine compared to GluN1/2B receptors in the presence of physiological Mg2+ . GluN2B-selective antagonists produce robust inhibition of GluN1/2B/2D receptors, and the GluN2B-selective positive allosteric modulator spermine enhances responses from GluN1/2B/2D but not GluN1/2A/2B receptors. These insights into the properties of triheteromeric GluN1/2B/2D receptors are necessary to appreciate their physiological roles in neural circuit function and the actions of therapeutic agents targeting NMDA receptors.AbstractTriheteromeric NMDA-type glutamate receptors that contain two GluN1 and two different GluN2 subunits contribute to excitatory neurotransmission in the adult CNS. In the present study, we report properties of the triheteromeric GluN1/2B/2D NMDA receptor subtype that is expressed in distinct neuronal populations throughout the CNS. We show that neither GluN2B, nor GluN2D dominate the functional properties of GluN1/2B/2D receptors because agonist potencies, open probability and the glutamate deactivation time course of GluN1/2B/2D receptors are intermediate to those of diheteromeric GluN1/2B and GluN1/2D receptors. Furthermore, channel blockade of GluN1/2B/2D by extracellular Mg2+ is intermediate compared to GluN1/2B and GluN1/2D, although GluN1/2B/2D is more sensitive to blockade by ketamine and memantine compared to GluN1/2B in the presence of physiological Mg2+ . Subunit-selective allosteric modulators have distinct activity at GluN1/2B/2D receptors, including GluN2B-selective antagonists, ifenprodil, EVT-101 and CP-101-606, which inhibit with similar potencies but with different efficacies at GluN1/2B/2D (∼65% inhibition) compared to GluN1/2B (∼95% inhibition). Furthermore, the GluN2B-selective positive allosteric modulator spermine enhances responses from GluN1/2B/2D but not GluN1/2A/2B receptors. We show that these key features of allosteric modulation of recombinant GluN1/2B/2D receptors are also observed for NMDA receptors in hippocampal interneurons but not CA1 pyramidal cells, which is consistent with the expression of GluN1/2B/2D receptors in interneurons and GluN1/2A/2B receptors in pyramidal cells. Altogether, we uncover previously unknown functional and pharmacological properties of triheteromeric GluN1/2B/2D receptors that can facilitate advances in our understanding of their physiological roles in neural circuit function and therapeutic drug actions.

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Triheteromeric NMDA receptors: from structure to synaptic physiology.

Publications

Triheteromeric NMDA receptors: from structure to synaptic physiology.

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