title: Pharmacology of triheteromeric N-Methyl-D-Aspartate Receptors.
abstract: The N-Methyl-D-Aspartate Receptors (NMDARs) are heteromeric cation channels involved in learning, memory, and synaptic plasticity, and their dysregulation leads to various neurodegenerative disorders. Recent evidence has shown that apart from the GluN1/GluN2A and GluN1/GluN2B diheteromeric ion channels, the NMDAR also exists as a GluN1/GluN2A/GluN2B triheteromeric channel that occupies the majority of the synaptic space. These GluN1/GluN2A/GluN2B triheteromers exhibit pharmacological and electrophysiological properties that are distinct from the GluN1/GluN2A and GluN1/GluN2B diheteromeric subtypes. However, these receptors have not been characterized with regards to their inhibition by conantokins, as well as their allosteric modulation by polyamines and extracellular protons. Here, we show that the GluN1/GluN2A/GluN2B triheteromeric channels showed less sensitivity to GluN2B-specific conantokin (con)-G and con-RlB, and subunit non-specific con-T, compared to the GluN2A-specific inhibitor TCN-201. Also, spermine modulation of GluN1/GluN2A/GluN2B triheteromers switched its nature from potentiation to inhibition in a pH dependent manner, and was 2.5-fold slower compared to the GluN1/GluN2B diheteromeric channels. Unraveling the distinctive functional attributes of the GluN1/GluN2A/GluN2B triheteromers is physiologically relevant since they form an integral part of the synapse, which will aid in understanding spermine/pH-dependent potentiation of these receptors in pathological settings.
authors.affiliation: W. M. Keck Center for Transgene Research and the Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN 46556, USA.
authors.forename: John
authors.initials: J
authors.lastname: Cheriyan
authors.affiliation: W. M. Keck Center for Transgene Research and the Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN 46556, USA.
authors.forename: Rashna D
authors.initials: RD
authors.lastname: Balsara
authors.affiliation: Department of Biomedical and Pharmaceutical Sciences, University of Montana, MT 59812, USA.
authors.forename: Kasper B
authors.initials: KB
authors.lastname: Hansen
authors.affiliation: W. M. Keck Center for Transgene Research and the Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN 46556, USA. Electronic address: fcastell@nd.edu.
authors.forename: Francis J
authors.initials: FJ
authors.lastname: Castellino
mesh_terms: D020916:Conotoxins / Q000494:pharmacology; D057809:HEK293 Cells; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D008978:Mollusk Venoms / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D010455:Peptides / Q000494:pharmacology; D055503:Protein Multimerization; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013096:Spermine / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology; D006834:Hydrazines; D000096926:Benzenesulfonamides
chemical_list: D020916:Conotoxins; D036341:Intercellular Signaling Peptides and Proteins; D008978:Mollusk Venoms; D010455:Peptides; D016194:Receptors, N-Methyl-D-Aspartate; D013096:Spermine; D013449:Sulfonamides; C409466:NR1 NMDA receptor; C121001:NR2B NMDA receptor; C574512:TCN 201; D006834:Hydrazines; D000096926:Benzenesulfonamides; C063571:conantokin-T; C055407:conotoxin GV
keywords: Contanokins; Diheteromers; NMDAR; Pharmacology; Triheteromers