title: GluN1-specific redox effects on the kinetic mechanism of NMDA receptor activation.
abstract: NMDA receptors are glutamate-activated ion channel complexes central to the functioning of the mammalian nervous system. Opening of the NMDA receptor ion channel pore is initiated by agonist-induced conformational changes in the extracellular ligand-binding domain (LBD) but the dynamic mechanism of this process remains unresolved. We studied how a disulfide bond in the obligatory GluN1 subunit-the sole site of redox modulation in NMDA receptors-controls this activation gating mechanism. This disulfide bond is located in the hinge region of the LBD, and presumably constrains agonist-induced cleft closure of the clamshell-like LBD. Elimination of this bond, by either DTT-mediated reduction or mutagenesis, enhances gating efficiency such that pore opening now occurs with higher frequency and longer duration. The most prominent effect was to shift opening modes to long duration openings reminiscent of a high P(o) gating mode that the NMDA receptor exhibits under ambient oxidizing conditions. In terms of preopen gating steps, elimination of this bond has effects only on the fast gating step consistent with this step being GluN1-specific and reflecting GluN1 gating movements immediately before channel opening. Overall, our results suggest that the dynamics of the GluN1 LBD have strong effects on late pore opening steps including regulating the duration of pore opening. This redox-mediated gating modulation could be an underlying mechanism of NMDA receptor malfunction in redox-dependent disease states and presents a potential target of pharmacologic action.
authors.affiliation: Graduate Program in Neuroscience, State University of New York at Stony Brook, Stony Brook, New York, USA.
authors.forename: Iehab
authors.initials: I
authors.lastname: Talukder
authors.forename: Rashek
authors.initials: R
authors.lastname: Kazi
authors.forename: Lonnie P
authors.initials: LP
authors.lastname: Wollmuth
mesh_terms: D000818:Animals; D003545:Cysteine / Q000378:metabolism; D004220:Disulfides / Q000378:metabolism; D004229:Dithiothreitol / Q000494:pharmacology; D015640:Ion Channel Gating / Q000187:drug effects; D007700:Kinetics; D008024:Ligands; D010084:Oxidation-Reduction / Q000187:drug effects; D017434:Protein Structure, Tertiary; D021122:Protein Subunits / Q000378:metabolism*; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D013997:Time Factors; D014981:Xenopus
chemical_list: D003545:Cysteine; D004220:Disulfides; D004229:Dithiothreitol; D008024:Ligands; D021122:Protein Subunits; D016194:Receptors, N-Methyl-D-Aspartate
references.citation: J Neurosci. 2000 Mar 15;20(6):2409-17
references.pmid: 10704515
references.citation: Neuron. 1994 Oct;13(4):929-36
references.pmid: 7524561
references.citation: J Gen Physiol. 2007 Jun;129(6):509-25
references.pmid: 17504910
references.citation: Nat Neurosci. 2003 May;6(5):476-83
references.pmid: 12679783
references.citation: Nature. 2002 May 16;417(6886):245-53
references.pmid: 12015593
references.citation: Nat Neurosci. 2009 Sep;12(9):1114-20
references.pmid: 19648915
references.citation: Proc Natl Acad Sci U S A. 1997 Sep 30;94(20):11019-24
references.pmid: 9380752
references.citation: EMBO J. 2003 Jun 16;22(12):2873-85
references.pmid: 12805203
references.citation: J Neurosci. 1997 Aug 1;17(15):5711-25
references.pmid: 9221770
references.citation: Proc R Soc Lond B Biol Sci. 1990 Jun 22;240(1299):453-77
references.pmid: 1696014
references.citation: Neuron. 1993 Nov;11(5):857-63
references.pmid: 8240809
references.citation: J Biol Chem. 2010 Apr 16;285(16):12334-43
references.pmid: 20110361
references.citation: J Physiol. 2005 Mar 1;563(Pt 2):345-58
references.pmid: 15649985
references.citation: J Neurosci. 2008 Jan 23;28(4):932-43
references.pmid: 18216201
references.citation: J Neurosci. 2006 Jul 19;26(29):7650-8
references.pmid: 16855092
references.citation: Nat Struct Mol Biol. 2011 Mar;18(3):283-7
references.pmid: 21317895
references.citation: J Pharmacol Exp Ther. 1999 Nov;291(2):785-92
references.pmid: 10525101
references.citation: Nat Chem Biol. 2005 Nov;1(6):329-32
references.pmid: 16408071
references.citation: J Neurosci. 2005 Aug 31;25(35):7914-23
references.pmid: 16135748
references.citation: J Neurosci. 2005 Apr 13;25(15):3752-62
references.pmid: 15829627
references.citation: J Neurosci. 2010 Jan 27;30(4):1463-70
references.pmid: 20107073
references.citation: J Neurosci. 2010 Sep 1;30(35):11792-804
references.pmid: 20810899
references.citation: J Neurosci. 2005 Jan 5;25(1):42-51
references.pmid: 15634765
references.citation: Brain Res. 1999 Jan 2;815(1):81-8
references.pmid: 9974125
references.citation: Curr Opin Neurobiol. 2011 Apr;21(2):283-90
references.pmid: 21349697
references.citation: J Biol Chem. 2000 Jul 14;275(28):21355-63
references.pmid: 10748170
references.citation: J Biol Chem. 2007 Jan 19;282(3):1863-72
references.pmid: 17105731
references.citation: J Neurosci. 2010 Sep 15;30(37):12474-9
references.pmid: 20844142
references.citation: Nat Neurosci. 2003 Feb;6(2):144-52
references.pmid: 12524545
references.citation: Neuron. 1994 May;12(5):1031-40
references.pmid: 7514425
references.citation: Pharmacol Rev. 2010 Sep;62(3):405-96
references.pmid: 20716669
references.citation: J Physiol. 2005 Dec 1;569(Pt 2):395-418
references.pmid: 16223763
references.citation: Curr Opin Neurobiol. 2001 Jun;11(3):327-35
references.pmid: 11399431
references.citation: Lancet Neurol. 2008 Aug;7(8):742-55
references.pmid: 18635022
references.citation: Nat Neurosci. 2008 Dec;11(12):1373-5
references.pmid: 18953348
references.citation: Neuron. 1989 Mar;2(3):1257-63
references.pmid: 2696504
references.citation: J Neurosci. 2009 May 27;29(21):6819-27
references.pmid: 19474309
references.citation: J Physiol. 1993 Jun;465:303-23
references.pmid: 7693919
references.citation: Structure. 2007 Oct;15(10):1203-14
references.pmid: 17937910
references.citation: J Neurosci. 2001 Jan 15;21(2):392-400
references.pmid: 11160420
references.citation: Nature. 2009 Dec 10;462(7274):745-56
references.pmid: 19946266
references.citation: Nature. 2004 Aug 12;430(7001):790-3
references.pmid: 15306812
references.citation: Curr Opin Pharmacol. 2007 Feb;7(1):39-47
references.pmid: 17088105
references.citation: Curr Drug Targets. 2007 May;8(5):573-82
references.pmid: 17504102