Key Points: Triheteromeric 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 Mg . 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.
Abstract: Triheteromeric 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 Mg 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 Mg . 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.
Download full-text PDF |
Source |
|---|---|
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6858497 | PMC |
| http://dx.doi.org/10.1113/JP278168 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Selective Cell-Surface Expression of Triheteromeric NMDA Receptors.
Methods Mol Biol
May 2024
Center for Structural and Functional Neuroscience, Center for Biomolecular Structure and Dynamics, Division of Biological Sciences, University of Montana, Missoula, MT, USA.
Article Synopsis
- NMDA receptors play a crucial role in brain functions and are linked to various brain disorders, composed of multiple subunits (GluN1, GluN2A-D, GluN3A-B) that form distinct receptor types.
- A method has been developed to precisely express triheteromeric NMDA receptors in laboratory settings, allowing researchers to control which subunits are present and avoid confusion from unintended receptor types.
- This technique has been successfully used to selectively express various triheteromeric receptor combinations, facilitating better investigation of their functional and pharmacological properties in the adult brain.
GluN2D Subunit in Parvalbumin Interneurons Regulates Prefrontal Cortex Feedforward Inhibitory Circuit and Molecular Networks Relevant to Schizophrenia.
Biol Psychiatry
August 2023
Department of Pharmacology and Neuroscience, Creighton University School of Medicine, Omaha, Nebraska. Electronic address:
Background: Parvalbumin interneuron (PVI) activity synchronizes the medial prefrontal cortex circuit for normal cognitive function, and its impairment may contribute to schizophrenia (SZ). NMDA receptors in PVIs participate in these activities and form the basis for the NMDA receptor hypofunction hypothesis of SZ. However, the role of the GluN2D subunit, which is enriched in PVIs, in regulating molecular networks relevant to SZ is unknown.
View Article and Find Full Text PDFPTC-174, a positive allosteric modulator of NMDA receptors containing GluN2C or GluN2D subunits.
Neuropharmacology
August 2020
BioPharmaWorks, LLC, Groton, CT, 06340, USA.
NMDA receptors are ionotropic glutamate receptors that mediate excitatory neurotransmission. The diverse functions of these receptors are tuned by deploying different combinations of GluN1 and GluN2 subunits (GluN2A-D) to form either diheteromeric NMDA receptors, which contain two GluN1 and two identical GluN2 subunits, or triheteromeric NMDA receptors, which contain two GluN1 and two distinct GluN2 subunits. Here, we characterize PTC-174, a novel positive allosteric modulator (PAM) of receptors containing GluN2C or GluN2D subunits.
View Article and Find Full Text PDFFunctional and pharmacological properties of triheteromeric GluN1/2B/2D NMDA receptors.
J Physiol
November 2019
Department of Biomedical and Pharmaceutical Sciences and Center for Structural and Functional Neuroscience, University of Montana, Missoula, MT, USA.
Key Points: Triheteromeric 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 Mg .
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!