title: Distinct functional and pharmacological properties of Triheteromeric GluN1/GluN2A/GluN2B NMDA receptors.
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 Zn(2+). 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.
authors.affiliation: Department of Pharmacology, Emory University School of Medicine, Atlanta, GA 30322, USA. Electronic address: kasper.hansen@mso.umt.edu.
authors.forename: Kasper B
authors.initials: KB
authors.lastname: Hansen
authors.affiliation: Department of Pharmacology, Emory University School of Medicine, Atlanta, GA 30322, USA.
authors.forename: Kevin K
authors.initials: KK
authors.lastname: Ogden
authors.affiliation: Department of Pharmacology, Emory University School of Medicine, Atlanta, GA 30322, USA.
authors.forename: Hongjie
authors.initials: H
authors.lastname: Yuan
authors.affiliation: Department of Pharmacology, Emory University School of Medicine, Atlanta, GA 30322, USA.
authors.forename: Stephen F
authors.initials: SF
authors.lastname: Traynelis
mesh_terms: D000818:Animals; D019281:Dimerization; D018691:Excitatory Amino Acid Antagonists / Q000378:metabolism / Q000494:pharmacology; D018698:Glutamic Acid / Q000502:physiology; D057809:HEK293 Cells; D006801:Humans; D009865:Oocytes / Q000166:cytology; D018408:Patch-Clamp Techniques; D010880:Piperidines / Q000378:metabolism / Q000494:pharmacology*; D011485:Protein Binding / Q000502:physiology; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics; D013449:Sulfonamides / Q000494:pharmacology; D014131:Trace Elements / Q000494:pharmacology; D014982:Xenopus laevis; D015032:Zinc / Q000494:pharmacology; D006834:Hydrazines; D000096926:Benzenesulfonamides
chemical_list: D018691:Excitatory Amino Acid Antagonists; D018698:Glutamic Acid; D010880:Piperidines; D016194:Receptors, N-Methyl-D-Aspartate; D011994:Recombinant Proteins; D013449:Sulfonamides; D014131:Trace Elements; D015032:Zinc; C121001:NR2B NMDA receptor; C574512:TCN 201; D006834:Hydrazines; D000096926:Benzenesulfonamides; C095106:traxoprodil mesylate; C010739:ifenprodil