Principal role of NR3 subunits in NR1/NR3 excitatory glycine receptor function

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

“…This bellshaped concentration-response relationship is presumably a result of glycine binding to unblocked GluN3 subunits at low glycine concentrations (rising phase). At higher glycine concentrations, the selective block by TK40 at GluN1 subunits is outcompeted, resulting in diminished receptor current (declining phase), which is in agreement with previous reports (41,42). For glycine-activated responses at wild-type GluN1/N3 receptors, we have previously reported that only negligible current responses (Ͻ10 nA) are observed at GluN1/N3A receptors upon glycine application and that glycine concentrations above 10 M result in diminished receptor current at GluN1/N3B receptors, thereby producing a bell-shaped concentration-response relationship (38).…”

“…4, panels B and C and panels E and F). The TK40-mediated potentiation of the glycine-activated current responses and the apparent shift in the bell-shaped concentration-response relationships presumably result from selective inhibition of glycine binding to the GluN1 subunit, which is in agreement with other reports (41,42).…”

“…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). Enhanced glycine activation of GluN1/N3 receptors has initially been shown by disrupting glycine binding to GluN1 via mutation of key amino acids in the GluN1 ligand-binding pocket (41,42).…”

“…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). Enhanced glycine activation of GluN1/N3 receptors has initially been shown by disrupting glycine binding to GluN1 via mutation of key amino acids in the GluN1 ligand-binding pocket (41,42). We have recently reported a method to isolate the GluN3 pharmacology of GluN1/N3 receptors by mutating the GluN1 subunit (i.e.…”

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.…”