Heteromeric NMDA Receptors: Molecular and Functional Distinction of Subtypes

TLDR

NMDA receptors are highly calcium‑permeable, voltage‑dependent magnesium‑sensitive ion channels modulated by glycine, with subunits NR1 and NR2 (NR2A, NR2B, NR2C) forming heteromeric complexes that are differentially expressed across the rat brain. Cloning revealed three NR2 subunits (NR2A, NR2B, NR2C) that, when co‑expressed with NR1, produce glutamate‑activated currents with distinct gating and magnesium sensitivity, indicating functional heterogeneity among NR1‑NR2A and NR1‑NR2C channels.

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.