The NMDA receptor intracellular C-terminal domains reciprocally interact with allosteric modulators.

The NMDA receptor intracellular C-terminal domains reciprocally interact with allosteric modulators. Biochem Pharmacol. 2018 Nov 29;: Authors: Sapkota K, Dore K, Tang K, Irvine M, Fang G, Burnell ES, Malinow R, Jane DE, Monaghan DT Abstract N-Methyl-D-aspartate receptors (NMDARs) have multiple prominent roles in CNS function but their excessive or insufficient activity contributes to neuropathological/psychiatric disorders. Consequently, a variety of positive and negative allosteric modulators (PAMs and NAMs, respectively) have recently been developed. Although these modulators bind to extracellular domains, in the present report we find that the NMDAR's intracellular C-terminal domains (CTDs) significantly influence PAM/NAM activity. GluN2 CTD deletion robustly affected NAM and PAM activity with both enhancing and inhibiting effects that were compound-specific and NMDAR subunit-specific. In three cases, individual PAMs became NAMs at specific GluN2-truncated receptors. In contrast to GluN2, GluN1 CTD removal only reduced PAM activity of UBP684 and CIQ, and did not affect NAM activity. Consistent with these findings, agents altering phosphorylation state or intracellular calcium levels displayed receptor-specific and compound-specific effects on PAM activity. It is possible that the GluN2's M4 domain transmits intracellular modulatory signals from the CTD to the M1/M4 channel gating machinery and that this site is a point of converge...
Source: Biochemical Pharmacology - Category: Drugs & Pharmacology Authors: Tags: Biochem Pharmacol Source Type: research