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

Research output: Contribution to journalArticle

Original languageEnglish
Pages (from-to)140-153
Number of pages14
JournalBiochemical Pharmacology
Volume159
Early online date29 Nov 2018
DOIs
DateAccepted/In press - 28 Nov 2018
DateE-pub ahead of print - 29 Nov 2018
DatePublished (current) - Jan 2019

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 convergence in the direct or indirect actions of several PAMs/NAMs thus rendering them sensitive to CTD status. Thus, allosteric modulators are likely to have a marked and varied sensitivity to post-translational modifications, protein-protein associations, and intracellular ions. The interaction between PAM activity and NMDAR CTDs appears reciprocal. GluN1 CTD-deletion eliminated UBP684, but not pregnenolone sulfate (PS), PAM activity. And, in the absence of agonists, UBP684, but not PS, was able to promote movement of fluorescently-tagged GluN1-CTDs. Thus, it may be possible to pharmacologically target NMDAR metabotropic activity in the absence of channel activation.

    Research areas

  • Allosteric modulators, C-terminal domain, Desensitization, Fluorescence resonance energy transfer, N-methyl-D-aspartate, Phosphorylation

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  • Full-text PDF (accepted author manuscript)

    Rights statement: This is the author accepted manuscript (AAM). The final published version (version of record) is available online via Elsevier at https://www.sciencedirect.com/science/article/pii/S0006295218304969#!. Please refer to any applicable terms of use of the publisher.

    Accepted author manuscript, 7.05 MB, PDF document

    Licence: CC BY-NC-ND

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