Distinct Functional and Pharmacological Properties of Triheteromeric GluN1/GluN2A/GluN2B NMDA Receptors

• Type of Material: Article
• Authors: Kasper B. Hansen, Emory University; Kevin K. Ogden, Emory University; Hongjie Yuan, Emory University; Stephen Traynelis, Emory University
• Language: English
• Date: 2014-03-05
• Publisher: Elsevier (Cell Press): 12 month embargo
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2014 Elsevier Inc. All rights reserved.
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1016/j.neuron.2014.01.035
• Title of Journal or Parent Work: Neuron
• ISSN: 0896-6273
• Volume: 81
• Issue: 5
• Start Page: 1084
• End Page: 1096
• Grant/Funding Information: This work was supported by NIH-NINDS grant NS036654; the Villum Kann Rasmussen Foundation; and the Lundbeck Foundation.
• Keywords: RAT CORTICAL-NEURONS; Science & Technology; Life Sciences & Biomedicine; Neurosciences & Neurology; ZINC INHIBITION; GABA(B) RECEPTOR; GLUTAMATE BINDING-SITE; NR2A SUBUNIT; Neurosciences; D-ASPARTATE RECEPTORS; HIPPOCAMPAL SYNAPSES; SYNAPTIC CURRENTS; MOLECULAR DETERMINANTS; TERMINAL DOMAIN
• Research Categories: Health Sciences, Pharmacy; Biology, Neuroscience

Abstract

NMDA receptors are tetrameric ligand-gated ion channels comprised of GluN1, GluN2, and GluN3 subunits. Two different GluN2 subunits have been identified in most NMDA receptor-expressing cells, and the majority of native receptors are triheteromers containing two GluN1 and two different GluN2. In contrast to diheteromeric NMDA receptors, little is known about the function of triheteromers. We developed a method to provide selective cell-surface expression of recombinant GluN1/GluN2A/GluN2B triheteromers and compared properties of these receptors with those of GluN1/GluN2A and GluN1/GluN2B diheteromers. We show that glutamate deactivation of triheteromers is distinct from those of GluN1/GluN2A and GluN1/GluN2B and reveal modulation of triheteromers by subunit-selective antagonists ifenprodil, CP-101,606, TCN-201, and extracellular Zn2+. Furthermore, kinetic measurements suggest variation in the ifenprodil binding site of triheteromers compared to GluN1/GluN2B diheteromers. This work provides insight into the distinct properties of GluN1/GluN2A/GluN2B triheteromers, which are presumably the most abundant NMDA receptors in the adult forebrain.