Excitatory glycine receptors containing the NR3 family of NMDA receptor subunits

Abstract

The N-methyl-D-aspartate subtype of glutamate receptor (NMDAR) serves critical functions in physiological and pathological processes in the central nervous system, including neuronal development, plasticity and neurodegeneration. Conventional heteromeric NMDARs composed of NR1 and NR2A-D subunits require dual agonists, glutamate and glycine, for activation. They are also highly permeable to Ca2+, and exhibit voltage-dependent inhibition by Mg2+. Coexpression of NR3A with NR1 and NR2 subunits modulates NMDAR activity. Here we report the cloning and characterization of the final member of the NMDAR family, NR3B, which shares high sequence homology with NR3A. From in situ and immunocytochemical analyses, NR3B is expressed predominantly in motor neurons, whereas NR3A is more widely distributed. Remarkably, when co-expressed in Xenopus oocytes, NR3A or NR3B co-assembles with NR1 to form excitatory glycine receptors that are unaffected by glutamate or NMDA, and inhibited by D-serine, a co-activator of conventional NMDARs. Moreover, NR1/NR3A or -3B receptors form relatively Ca2+-impermeable cation channels that are resistant to Mg2+, MK-801, memantine and competitive antagonists. In cerebrocortical neurons containing NR3 family members, glycine triggers a burst of firing, and membrane patches manifest glycine-responsive single channels that are suppressible by D-serine. By itself, glycine is normally thought of as an inhibitory neurotransmitter. In contrast, these NR1/NR3A or -3B 'NMDARs' constitute a type of excitatory glycine receptor.

Distinct proteomic profiles of amphetamine self-administration transitional states

“…NR3A is a relatively calciumimpermeable ionotropic receptor that forms heteromers with NR1 and serves as an excitatory glycine receptor. 40 Previously, NR3A expression has been reported in the rat retrohippocampal region, with highest expression in the vSub. 41 Another glutamate-related change observed was an increase in aspartate aminotransferase (AST), which was also evident only in the Abstinent rats.…”

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

“…To evaluate the selectivity between the glycine-binding GluN1 and GluN3 subunits, TK40 was also characterized at GluN1(F484A/T518L)/N3A and GluN1(F484A/ T518L)/N3B receptors. Diheteromeric GluN1/N3 receptors are activated by glycine that binds to both the GluN1 and GluN3 subunits (23,24,39,40). Glycine has dual activity at the GluN1/N3 receptors, in that glycine appears to act agonistically at the GluN3 subunit and inhibitory through binding to the GluN1 subunit (41,42), but agonist binding to the GluN3 subunits alone is sufficient to activate the receptor (41, 42).…”

N-methyl-d-aspartate receptor inhibition by an apolipoprotein E-derived peptide relies on low-density lipoprotein receptor-associated protein

“…Functional NMDARs are comprised of several types of subunits, viz., an obligatory NR1 subunit, of which there are eight splice variants (1a/b-4 a/b) (Hollmann et al, 1993;Zukin and Bennett, 1995), and one or more regulatory NR2 (A-D) subunits (Molinoff et al, 1994) and/or NR3 subunits (Das et al, 1998;Chatterton et al, 2002;Madry et al, 2007).NR subunits are expressed temporally and regionally in the central nervous system and the nature of the subunit associations in the functional NMDAR control the properties of this receptor (Paoletti and Neyton, 2007;Prorok and Castellino, 2007). Some functions of apoE have been linked to those of the NMDAR.…”