Heteromeric NMDA Receptors: Molecular and Functional Distinction of Subtypes

Abstract

The N-methyl D-aspartate (NMDA) receptor subtype of glutamate-gated ion channels possesses high calcium permeability and unique voltage-dependent sensitivity to magnesium and is modulated by glycine. Molecular cloning identified three complementary DNA species of rat brain, encoding NMDA receptor subunits NMDAR2A (NR2A), NR2B, and NR2C, which are 55 to 70% identical in sequence. These are structurally related, with less than 20% sequence identity, to other excitatory amino acid receptor subunits, including the NMDA receptor subunit NMDAR1 (NR1). Upon expression in cultured cells, the new subunits yielded prominent, typical glutamate- and NMDA-activated currents only when they were in heteromeric configurations with NR1. NR1-NR2A and NR1-NR2C channels differed in gating behavior and magnesium sensitivity. Such heteromeric NMDA receptor subtypes may exist in neurons, since NR1 messenger RNA is synthesized throughout the mature rat brain, while NR2 messenger RNA show a differential distribution.

Estrogen-like Activity of Tamoxifen and Raloxifene on NMDA Receptor Binding and Expression of its Subunits in Rat Brain

“…In situ hybridization was performed using previously published sequences of oligonucleotides (Monyer et al 1992) complementary to rat cRNA encoding subunits residues between transmembrane domains I and II, encoding amino acids 566-580 of the mature peptide NMDA receptors subunit 1 (5'-TTCCTCCTCCTCCTCACTGT-TCACCTTGAATCGGCCAAAGGGACT-3'), 567-579 of the NMDA receptors subunit 2A (5'-AGAAGGCCC-GTGGGGAGCTTTCCCTTTGGCTAAGTTTC-3'), and 557-572 of the NMDA receptors subunit 2B (5'-GGG-CCTCCTGGCTCTCTGCCATCGGCTAGGCACCTGTT-GTAACCC-3'); note that the sequence of the oligonucleotide against NMDA receptor subunit 1 mRNA detects a population of eight distinct isoforms of a number of alternative splice variants (Sugihara et al 1992;Hollmann et al 1993). Oligonucleotides were 3' end-labeled with terminal transferase (Boehringer Mannheim) using 20 pmol cDNA and 50 Ci [␣-35 S] dATP (1200-1400 Ci/mmol; NEN).…”

“…The measurements of the total area of eight adjacent sections of the pyramidal cell layer of the hippocampal CA1 and CA2/3 regions and the molecular layer dentate gyrus (Bregma Ϫ4.20 mm) (Paxinos and Watson 1982) were performed to evaluate NMDA receptor subunits 1, 2A, and 2B mRNA levels. In situ hybridization to evaluate NMDA receptors subunits 2A and 2B mRNA levels in cortical and striatal regions of the brain was not performed because of the lower level of expression found in these regions (Moriyoshi et al 1991, Monyer et al 1992. Examples are shown in Figure 2.…”

Organization of Ionotropic Glutamate Receptors at Dendrodendritic Synapses in the Rat Olfactory Bulb

“…The distribution of NMDA receptors in the EPL was investigated with an antiserum against the NR1 subunit, the obligatory subunit for all functional NMDA receptors (Moriyoshi et al, 1991;Kutsuwada et al, 1992;Meguro et al, 1992;Monyer et al, 1992) (for review, see Nakanishi, 1992). Most of the immunoparticles representing the NR1 subunit were associated with asymmetric synapses and were usually not present at symmetric junctions (Fig.…”

Association between NMDA receptor subunit 2b gene polymorphism and Alzheimer’s disease in Chinese Han population in Shanghai

“…NMDA receptor is a tetramer composed of 2 NR1 subunits and 2 NR2 subunits, and less commonly, a NR3 subunit in addition [9] . The NR1 subunit is necessary for functional NMDA receptor channel while the NR2 subunits, identified as NR2A, NR2B, NR2C and NR2D isoforms, function to interact with glutamate and many other important modulating molecules.…”