Functional evidence for a twisted conformation of the NMDA receptor GluN2A subunit N-terminal domain

Neuropharmacology
David StroebelPierre Paoletti

Abstract

Ionotropic glutamate receptors (iGluRs) possess in their extracellular region a large N-terminal domain (NTD) that precedes the agonist-binding domain and displays a clamshell-like architecture similar to the bacterial leucine/isoleucine/valine-binding protein (LIVBP). In addition to their role in receptor assembly, in NMDA receptors (NMDARs), the NTDs of GluN2A and GluN2B subunits form a major site for subunit-specific regulation of ion channel activity, in particular through binding of allosteric modulators such as the synaptically-enriched zinc ion. A recent crystallographic study of the isolated GluN2B NTD has revealed an unexpected twisted closed-cleft conformation caused by a rotation of ∼ 50° in the interlobe orientation compared with all other known LIVBP-like structures (Karakas et al., 2009). By measuring currents carried by recombinant NMDARs, we now provide functional evidence, through disulfide cross-linking and the identification of a new zinc-binding residue (D283), that the GluN2A NTD of intact GluN1/GluN2A receptors adopts a similar twisted conformation in its closed-cleft state. We propose that the twisted NTD conformation is a distinct structural feature of NMDARs (at least for GluN2A and GluN2B subunits), ar...Continue Reading

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Citations

Mar 5, 2013·Nature Structural & Molecular Biology·Shujia ZhuPierre Paoletti
Jul 13, 2011·The Journal of General Physiology·Iehab Talukder, Lonnie P Wollmuth
Apr 12, 2012·PloS One·Morgane RiouPierre Paoletti
Aug 10, 2012·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Amy J GleichmanDavid R Lynch
Aug 5, 2011·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Catherine L SalussoliaLonnie P Wollmuth
Mar 11, 2011·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Anthony N FarinaTerunaga Nakagawa
Sep 15, 2012·Annual Review of Physiology·Janesh Kumar, Mark L Mayer
Nov 23, 2011·The Journal of Physiology·Hiro Furukawa
Mar 15, 2011·The European Journal of Neuroscience·Pierre Paoletti
Feb 5, 2013·Neuropharmacology·D J A WyllieG E Hardingham
Dec 3, 2014·Current Opinion in Pharmacology·Shujia Zhu, Pierre Paoletti
Aug 14, 2020·The Journal of Physiology·David Stroebel, Pierre Paoletti
Jan 6, 2015·The Journal of Physiology·Nathan G GlasgowJon W Johnson

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