Functional Characterization of Human N‐Methyl‐d‐Aspartate Subtype 1A/2D Receptors

Abstract

The human NMDAR2D subunit was cloned, and the pharmacological properties of receptors resulting from injection of transcripts encoding human NMDAR1A and NMDAR2D subunits in Xenopus oocytes were characterized by profiling NMDA receptor agonists and antagonists. We found that glutamate, NMDA, glycine, and d‐serine were significantly more potent on hNMDAR1A/2D than on hNMDAR1A/2A or hNMDAR1A/2B. Also, the potencies of NMDA and glycine were higher for hNMDAR1A/2D than for hNMDAR1A/2C. Ifenprodil was more potent at hNMDAR1A/2B than at hNMDAR1A/2D, whereas 5,7‐dichlorokynurenate was more potent at hNMDAR1A/2A than at hNMDAR1A/2D. As measured in transiently transfected human embryonic kidney 293 cells, the maximal inward current in the presence of external Mg2+ occurred at −40 mV, and full block was not observed at negative potentials. Kinetic measurements revealed that the higher affinity of hNMDAR1A/2D for both glutamate and glycine relative to hNMDAR1A/2A and hNMDA1A/2B can be explained by slower dissociation of each agonist from hNMDAR1A/2D. The hNMDAR1A/2D combination represents a pharmacologically and functionally distinct receptor subtype and may constitute a potentially important target for therapeutic agents active in the human CNS.

Crystal Structure and Pharmacological Characterization of a Novel N-Methyl-d-aspartate (NMDA) Receptor Antagonist at the GluN1 Glycine Binding Site

“…The K i value of 5,7-DCKA at GluN1/ N2A obtained here correlates nicely with estimated K i values (30 -170 nM) reported for 5,7-DCKA at the four recombinant GluN1/N2 receptors (44). Furthermore, we report here the first functional data displaying selectivity of 5,7-DCKA for GluN1 over GluN3 subunits, which are consistent with previously reported binding studies of the isolated soluble LBDs of GluN1 and GluN3A.…”

Glutamate Receptor Ion Channels: Structure, Regulation, and Function

“…Ifenprodil inhibits GluN2B-containing receptors with high affinity and is 200 to 400-fold more potent for GluN1/GluN2B receptors than for GluN1/GluN2A, GluN1/GluN2C, or GluN1/ GluN2D receptors (Williams, 1993;Hess et al, 1998; IC 50 ϳ150 nM). GluN1 splice variants do not influence the ability of ifenprodil to inhibit GluN2B-containing receptors , but triheteromeric receptors containing GluN1/GluN2A/GluN2B are proposed to be less sensitive to ifenprodil (Hatton and Paoletti, 2005), and insensitive to CP-101,606 (Brimecombe et al, 1997;Chazot et al, 2002).…”

The genetics of bipolar disorder: genome ‘hot regions,’ genes, new potential candidates and future directions

“…It is involved in long-term potentiation and in activity-dependent increase in the efficiency of synaptic transmission and it is thought to underlie certain kinds of memory and learning. 353 Recently, two studies investigated this gene in BP, reporting positive findings, particularly in association with psychotic symptoms.…”