A novel NMDA receptor positive allosteric modulator that acts via the transmembrane domain

Ionotropic glutamate receptors (iGluRs) mediate fast excitatory neurotransmission and are key nervous system drug targets. While diverse pharmacological tools have yielded insight into iGluR extracellular domain function, less is known about molecular mechanisms underlying the ion conduction gating...

Full description

Saved in:

Bibliographic Details
Published in	Neuropharmacology Vol. 121; pp. 204 - 218
Main Authors	Wang, Tzu-Ming, Brown, Brandon M., Deng, Lunbin, Sellers, Benjamin D., Lupardus, Patrick J., Wallweber, Heidi J.A., Gustafson, Amy, Wong, Evera, Volgraf, Matthew, Schwarz, Jacob B., Hackos, David H., Hanson, Jesse E.
Format	Journal Article
Language	English
Published	England Elsevier Ltd 15.07.2017
Subjects	Allosteric Regulation - drug effects Allosteric Regulation - genetics Binding Sites - drug effects Binding Sites - genetics Calcium - metabolism Dose-Response Relationship, Drug Doxycycline - pharmacology Electric Stimulation Excitatory Amino Acid Agents - chemistry Excitatory Amino Acid Agents - pharmacology Glutamic Acid - pharmacology Glycine - metabolism HEK293 Cells Humans Membrane Potentials - drug effects Membrane Potentials - genetics NMDA receptor Patch-Clamp Techniques Positive allosteric modulator Protein Domains - drug effects Protein Domains - genetics Pyrimidinones - chemistry Pyrimidinones - pharmacology Receptors, N-Methyl-D-Aspartate - genetics Receptors, N-Methyl-D-Aspartate - metabolism Sulfonamides - chemistry Sulfonamides - pharmacology Synaptic Transmission - drug effects Synaptic Transmission - genetics Synaptic Transmission - physiology Transfection Transmembrane domain Ifenprodil (PubChem CID GNE-8016 (PubChem CID iGluR 118009479 20938953 4231127 Transmembrane domain 22432385 TMD GNE-3419 (PubChem CID LBD ATD GNE-9278 (PubChem CID Positive allosteric modulator NAM NMDA receptor 3689 PAM CIQ (PubChem CID
Online Access	Get full text

Cover

Loading…

Abstract	Ionotropic glutamate receptors (iGluRs) mediate fast excitatory neurotransmission and are key nervous system drug targets. While diverse pharmacological tools have yielded insight into iGluR extracellular domain function, less is known about molecular mechanisms underlying the ion conduction gating process within the transmembrane domain (TMD). We have discovered a novel NMDAR positive allosteric modulator (PAM), GNE-9278, with a unique binding site on the extracellular surface of the TMD. Mutation of a single residue near the Lurcher motif on GluN1 M3 can convert GNE-9278 modulation from positive to negative, and replacing three AMPAR pre-M1 residues with corresponding NMDAR residues can confer GNE-9278 sensitivity to AMPARs. Modulation by GNE-9278 is state-dependent and significantly alters extracellular domain pharmacology. The unique properties and structural determinants of GNE-9278 reveal new modulatory potential of the iGluR TMD. •GNE-9278 is a NMDAR positive allosteric modulator that acts at the GluN1 TMD.•GNE-9278 acts on activated NMDARs to increase peak current and agonist affinity.•TMD point mutations can convert GNE-9278 modulation from positive to negative.•TMD point mutations can confer GNE-9278 potentiation to AMPARs.•GNE-9278 modulation is state-dependent and alters extracellular domain pharmacology.
AbstractList	Ionotropic glutamate receptors (iGluRs) mediate fast excitatory neurotransmission and are key nervous system drug targets. While diverse pharmacological tools have yielded insight into iGluR extracellular domain function, less is known about molecular mechanisms underlying the ion conduction gating process within the transmembrane domain (TMD). We have discovered a novel NMDAR positive allosteric modulator (PAM), GNE-9278, with a unique binding site on the extracellular surface of the TMD. Mutation of a single residue near the Lurcher motif on GluN1 M3 can convert GNE-9278 modulation from positive to negative, and replacing three AMPAR pre-M1 residues with corresponding NMDAR residues can confer GNE-9278 sensitivity to AMPARs. Modulation by GNE-9278 is state-dependent and significantly alters extracellular domain pharmacology. The unique properties and structural determinants of GNE-9278 reveal new modulatory potential of the iGluR TMD. •GNE-9278 is a NMDAR positive allosteric modulator that acts at the GluN1 TMD.•GNE-9278 acts on activated NMDARs to increase peak current and agonist affinity.•TMD point mutations can convert GNE-9278 modulation from positive to negative.•TMD point mutations can confer GNE-9278 potentiation to AMPARs.•GNE-9278 modulation is state-dependent and alters extracellular domain pharmacology. Ionotropic glutamate receptors (iGluRs) mediate fast excitatory neurotransmission and are key nervous system drug targets. While diverse pharmacological tools have yielded insight into iGluR extracellular domain function, less is known about molecular mechanisms underlying the ion conduction gating process within the transmembrane domain (TMD). We have discovered a novel NMDAR positive allosteric modulator (PAM), GNE-9278, with a unique binding site on the extracellular surface of the TMD. Mutation of a single residue near the Lurcher motif on GluN1 M3 can convert GNE-9278 modulation from positive to negative, and replacing three AMPAR pre-M1 residues with corresponding NMDAR residues can confer GNE-9278 sensitivity to AMPARs. Modulation by GNE-9278 is state-dependent and significantly alters extracellular domain pharmacology. The unique properties and structural determinants of GNE-9278 reveal new modulatory potential of the iGluR TMD.
Author	Wang, Tzu-Ming Deng, Lunbin Wallweber, Heidi J.A. Schwarz, Jacob B. Volgraf, Matthew Brown, Brandon M. Hanson, Jesse E. Hackos, David H. Sellers, Benjamin D. Wong, Evera Lupardus, Patrick J. Gustafson, Amy
Author_xml	– sequence: 1 givenname: Tzu-Ming surname: Wang fullname: Wang, Tzu-Ming organization: Department of Neuroscience, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, United States – sequence: 2 givenname: Brandon M. surname: Brown fullname: Brown, Brandon M. organization: Department of Neuroscience, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, United States – sequence: 3 givenname: Lunbin surname: Deng fullname: Deng, Lunbin organization: Department of Neuroscience, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, United States – sequence: 4 givenname: Benjamin D. surname: Sellers fullname: Sellers, Benjamin D. organization: Department of Discovery Chemistry, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, United States – sequence: 5 givenname: Patrick J. surname: Lupardus fullname: Lupardus, Patrick J. organization: Department of Structural Biology, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, United States – sequence: 6 givenname: Heidi J.A. surname: Wallweber fullname: Wallweber, Heidi J.A. organization: Department of Structural Biology, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, United States – sequence: 7 givenname: Amy surname: Gustafson fullname: Gustafson, Amy organization: Department of Biochemical and Cellular Pharmacology, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, United States – sequence: 8 givenname: Evera surname: Wong fullname: Wong, Evera organization: Department of Neuroscience, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, United States – sequence: 9 givenname: Matthew surname: Volgraf fullname: Volgraf, Matthew organization: Department of Discovery Chemistry, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, United States – sequence: 10 givenname: Jacob B. surname: Schwarz fullname: Schwarz, Jacob B. organization: Department of Discovery Chemistry, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, United States – sequence: 11 givenname: David H. surname: Hackos fullname: Hackos, David H. email: hackos.david@gene.com organization: Department of Neuroscience, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, United States – sequence: 12 givenname: Jesse E. surname: Hanson fullname: Hanson, Jesse E. email: hanson.jesse@gene.com organization: Department of Neuroscience, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, United States
BackLink	https://www.ncbi.nlm.nih.gov/pubmed/28457974$$D View this record in MEDLINE/PubMed
BookMark	eNqFkMlOwzAQhi0EgrK8AvILpNiJUzvHsiOxXODCxRrHE-EqiSPbrcTb46osR6SRRqP5_1m-Y7I_-hEJoZzNOeOLi9V8xHXw0weEYV4yLudM5OB7ZMaVrArJFmKfzBgrVVE1TB2R4xhXjDGhuDokR6UStWykmJH3JR39Bnv6_HS9pAFbnJIPdPLRJbdBCn3vY8LgWjp4u-5h200fkCi0KdKNg1whTQHGOOBgckZq_QBuPCUHHfQRz77zCXm7vXm9ui8eX-4erpaPRStKkQqpTIuswYorK4y0Xb5Rlp2Bsm6a2oBZWANKgrVopYGqhKaUtcFOQs2sWlQnRO3mtsHHGLDTU3ADhE_Nmd7i0iv9h0tvcWkmcvBsPd9Zp7UZ0P4af_hkweVOgPmBjcOgY-twbNG6zCpp693_W74AQj2FhQ
CitedBy_id	crossref_primary_10_1016_j_cophys_2017_12_003 crossref_primary_10_1021_acs_jmedchem_2c00313 crossref_primary_10_1038_s41589_019_0449_5 crossref_primary_10_1021_acs_jmedchem_9b00591 crossref_primary_10_1016_j_pep_2022_106129 crossref_primary_10_1021_acs_jmedchem_0c01304 crossref_primary_10_1113_JP278086 crossref_primary_10_1016_j_neuropharm_2023_109703 crossref_primary_10_1016_j_neuropharm_2020_108117 crossref_primary_10_1021_acsmedchemlett_8b00450 crossref_primary_10_1111_bph_15841 crossref_primary_10_1007_s00018_022_04667_7 crossref_primary_10_1038_s41386_023_01614_3 crossref_primary_10_1101_gr_275528_121 crossref_primary_10_1124_pharmrev_120_000131 crossref_primary_10_7554_eLife_34711 crossref_primary_10_1002_npr2_12306 crossref_primary_10_1186_s12888_019_2306_1 crossref_primary_10_2174_1568026619666191011095341 crossref_primary_10_1085_jgp_201812234 crossref_primary_10_1113_JP280875 crossref_primary_10_1016_j_scr_2018_02_002 crossref_primary_10_1021_acs_jmedchem_8b01651 crossref_primary_10_1021_acs_jmedchem_9b01733 crossref_primary_10_1021_acs_jmedchem_7b01640 crossref_primary_10_1016_j_apsb_2024_01_004
Cites_doi	10.1124/mol.107.044115 10.1093/schbul/sbs010 10.1038/nature13548 10.1016/j.neuropharm.2016.07.037 10.1038/nrn3504 10.1124/jpet.104.077388 10.1073/pnas.0401838101 10.1016/j.coph.2014.10.009 10.1523/JNEUROSCI.3175-07.2007 10.1085/jgp.201210786 10.1038/417245a 10.4161/cib.27887 10.1016/j.neuron.2005.09.024 10.1523/JNEUROSCI.3485-07.2008 10.1124/pr.109.002451 10.1016/j.neuron.2016.01.016 10.1523/JNEUROSCI.0660-04.2004 10.1038/ncomms1085 10.1038/srep10935 10.1196/annals.1300.020 10.1016/j.neuron.2016.08.012 10.1523/JNEUROSCI.2567-05.2005 10.1124/mol.113.085209 10.1016/j.neuropharm.2013.03.030 10.1126/science.1258409 10.1085/jgp.200609718 10.1113/jphysiol.1995.sp020591 10.1124/mol.61.3.533 10.1126/science.1251915 10.1021/acs.jmedchem.5b02010 10.1038/73877 10.1038/42009
ContentType	Journal Article
Copyright	2017 The Authors Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.
Copyright_xml	– notice: 2017 The Authors – notice: Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.
DBID	6I. AAFTH CGR CUY CVF ECM EIF NPM AAYXX CITATION
DOI	10.1016/j.neuropharm.2017.04.041
DatabaseName	ScienceDirect Open Access Titles Elsevier:ScienceDirect:Open Access Medline MEDLINE MEDLINE (Ovid) MEDLINE MEDLINE PubMed CrossRef
DatabaseTitle	MEDLINE Medline Complete MEDLINE with Full Text PubMed MEDLINE (Ovid) CrossRef
DatabaseTitleList	MEDLINE
Database_xml	– sequence: 1 dbid: NPM name: PubMed url: https://proxy.k.utb.cz/login?url=http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed sourceTypes: Index Database – sequence: 2 dbid: EIF name: MEDLINE url: https://proxy.k.utb.cz/login?url=https://www.webofscience.com/wos/medline/basic-search sourceTypes: Index Database
DeliveryMethod	fulltext_linktorsrc
Discipline	Pharmacy, Therapeutics, & Pharmacology
EISSN	1873-7064
EndPage	218
ExternalDocumentID	10_1016_j_neuropharm_2017_04_041 28457974 S0028390817301910
Genre	Journal Article
GroupedDBID	--- --K --M -~X .~1 0R~ 123 1B1 1RT 1~. 1~5 4.4 457 4G. 5RE 6I. 7-5 71M 8P~ 9JM AABNK AACTN AADPK AAEDT AAEDW AAFTH AAIAV AAIKJ AAKOC AALRI AAOAW AATCM AAXLA AAXUO ABCQJ ABFRF ABIVO ABJNI ABMAC ABYKQ ABZDS ACDAQ ACGFO ACGFS ACIUM ACRLP ADBBV ADEZE AEBSH AEFWE AEKER AENEX AFKWA AFTJW AFXIZ AGUBO AGWIK AGYEJ AHHHB AIEXJ AIKHN AITUG AJBFU AJOXV ALCLG ALMA_UNASSIGNED_HOLDINGS AMFUW AMRAJ AXJTR BKOJK BLXMC C45 CS3 DU5 EBS EFJIC EFLBG EJD EO8 EO9 EP2 EP3 F5P FDB FIRID FNPLU FYGXN G-Q GBLVA IHE J1W K-O KOM L7B M2V M34 M41 MO0 MOBAO N9A O-L O9- OAUVE OGGZJ OVD OZT P-8 P-9 P2P PC. Q38 RIG ROL RPZ SCC SDF SDG SDP SES SNS SPCBC SSN SSP SSZ T5K TEORI ~G- AAQFI AAXKI AKRWK CGR CUY CVF ECM EIF NPM .55 .GJ 29N 3O- 41~ 53G 5VS AAQXK AAYXX ABFNM ABXDB ACRPL ADIYS ADMUD ADNMO AFJKZ AGHFR ASPBG AVWKF AZFZN CITATION FEDTE FGOYB G-2 HMQ HMT HVGLF HZ~ R2- SEW SPT WUQ X7M XOL ZGI ZXP
ID	FETCH-LOGICAL-c424t-78bce09e318d4b7df48172fba25995bab6dba87added7ba32a9275bef7a50d863
IEDL.DBID	AIKHN
ISSN	0028-3908
IngestDate	Fri Dec 06 00:25:47 EST 2024 Sat Sep 28 07:59:56 EDT 2024 Fri Feb 23 02:30:55 EST 2024
IsDoiOpenAccess	true
IsOpenAccess	true
IsPeerReviewed	true
IsScholarly	true
Keywords	Ifenprodil (PubChem CID GNE-8016 (PubChem CID iGluR 118009479 20938953 4231127 Transmembrane domain 22432385 TMD GNE-3419 (PubChem CID LBD ATD GNE-9278 (PubChem CID Positive allosteric modulator NAM NMDA receptor 3689 PAM CIQ (PubChem CID
Language	English
License	This is an open access article under the CC BY license. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.
LinkModel	DirectLink
MergedId	FETCHMERGED-LOGICAL-c424t-78bce09e318d4b7df48172fba25995bab6dba87added7ba32a9275bef7a50d863
OpenAccessLink	https://www.sciencedirect.com/science/article/pii/S0028390817301910
PMID	28457974
PageCount	15
ParticipantIDs	crossref_primary_10_1016_j_neuropharm_2017_04_041 pubmed_primary_28457974 elsevier_sciencedirect_doi_10_1016_j_neuropharm_2017_04_041
PublicationCentury	2000
PublicationDate	2017-07-15
PublicationDateYYYYMMDD	2017-07-15
PublicationDate_xml	– month: 07 year: 2017 text: 2017-07-15 day: 15
PublicationDecade	2010
PublicationPlace	England
PublicationPlace_xml	– name: England
PublicationTitle	Neuropharmacology
PublicationTitleAlternate	Neuropharmacology
PublicationYear	2017
Publisher	Elsevier Ltd
Publisher_xml	– name: Elsevier Ltd
References	Chang, Kuo (bib4) 2008; 28 Kashiwagi, Masuko, Nguyen, Kuno, Tanaka, Igarashi, Williams (bib15) 2002; 61 Volgraf (bib29) 2016 Mar; 59 Balannik, Menniti, Paternain, Lerma, Stern-Bach (bib1) 2005; 48 Coyle, Tsai, Goff (bib6) 2003; 1003 Hu, Zheng (bib11) 2005; 312 Zhou, Sheng (bib32) 2013; 74 Blanke, VanDongen (bib3) 2008; 74 Schmid, Korber, Herrmann, Werner, Hollmann (bib24) 2007; 27 Paoletti, Bellone, Zhou (bib23) 2013; 14 Zhu, Paoletti (bib33) 2015; 20 Zuo, De Jager, Takahashi, Jiang, Linden, Heintz (bib34) 1997; 388 Gonzalez-Burgos, Lewis (bib8) 2012; 38 Traynelis, Wollmuth, McBain, Menniti, Vance, Ogden, Hansen, Yuan, Myers, Dingledine (bib28) 2010; 62 Kohda, Wang, Yuzaki (bib17) 2000; 3 Dingledine, Borges, Bowie, Traynelis (bib7) 1999; 51 Vyklicky, Krausova, Cerny, Balik, Zapotocky, Novotny, Lichnerova, Smejkalova, Kaniakova, Korinek, Petrovic, Kacer, Horak, Chodounska, Vyklicky (bib30) 2015; 5 Lee, Lu, Michel, Goehring, Du, Song, Gouaux (bib18) 2014; 511 Jang, Mierke, Russek, Farb (bib12) 2004; 101 Karakas, Furukawa (bib14) 2014; 344 Ogden, Traynelis (bib22) 2013; 83 Yelshanskaya, Singh, Sampson, Narangoda, Kurnikova, Sobolevsky (bib31) 2016; 91 Soto, Altafaj, Sindreu, Bayes (bib26) 2014; 7 Hackos, Lupardus, Grand, Chen, Wang, Reynen, Gustafson, Wallweber, Volgraf, Sellers, Schwarz, Paoletti, Sheng, Zhou, Hanson (bib10) 2016; 89 Sobolevsky, Prodromou, Yelshansky, Wollmuth (bib25) 2007; 129 Hackos, Hanson (bib9) 2017 Jan; 112 Jin, Clark, Weeks, Dudman, Gouaux, Partin (bib13) 2005; 25 Chen, Durr, Gouaux (bib5) 2014; 345 Benveniste, Mayer (bib2) 1995; 483 Klein, Howe (bib16) 2004; 24 Sun, Olson, Horning, Armstrong, Mayer, Gouaux (bib27) 2002; 417 Mullasseril, Hansen, Vance, Ogden, Yuan, Kurtkaya, Santangelo, Orr, Le, Vellano, Liotta, Traynelis (bib19) 2010; 1 Murthy, Shogan, Page, Kasperek, Popescu (bib20) 2012; 140 Balannik (10.1016/j.neuropharm.2017.04.041_bib1) 2005; 48 Kashiwagi (10.1016/j.neuropharm.2017.04.041_bib15) 2002; 61 Volgraf (10.1016/j.neuropharm.2017.04.041_bib29) 2016; 59 Hackos (10.1016/j.neuropharm.2017.04.041_bib9) 2017; 112 Karakas (10.1016/j.neuropharm.2017.04.041_bib14) 2014; 344 Lee (10.1016/j.neuropharm.2017.04.041_bib18) 2014; 511 Zhou (10.1016/j.neuropharm.2017.04.041_bib32) 2013; 74 Vyklicky (10.1016/j.neuropharm.2017.04.041_bib30) 2015; 5 Chen (10.1016/j.neuropharm.2017.04.041_bib5) 2014; 345 Jin (10.1016/j.neuropharm.2017.04.041_bib13) 2005; 25 Traynelis (10.1016/j.neuropharm.2017.04.041_bib28) 2010; 62 Benveniste (10.1016/j.neuropharm.2017.04.041_bib2) 1995; 483 Schmid (10.1016/j.neuropharm.2017.04.041_bib24) 2007; 27 Zuo (10.1016/j.neuropharm.2017.04.041_bib34) 1997; 388 Yelshanskaya (10.1016/j.neuropharm.2017.04.041_bib31) 2016; 91 Murthy (10.1016/j.neuropharm.2017.04.041_bib20) 2012; 140 Kohda (10.1016/j.neuropharm.2017.04.041_bib17) 2000; 3 Sun (10.1016/j.neuropharm.2017.04.041_bib27) 2002; 417 Gonzalez-Burgos (10.1016/j.neuropharm.2017.04.041_bib8) 2012; 38 Paoletti (10.1016/j.neuropharm.2017.04.041_bib23) 2013; 14 Dingledine (10.1016/j.neuropharm.2017.04.041_bib7) 1999; 51 Ogden (10.1016/j.neuropharm.2017.04.041_bib22) 2013; 83 Zhu (10.1016/j.neuropharm.2017.04.041_bib33) 2015; 20 Blanke (10.1016/j.neuropharm.2017.04.041_bib3) 2008; 74 Soto (10.1016/j.neuropharm.2017.04.041_bib26) 2014; 7 Hackos (10.1016/j.neuropharm.2017.04.041_bib10) 2016; 89 Sobolevsky (10.1016/j.neuropharm.2017.04.041_bib25) 2007; 129 Klein (10.1016/j.neuropharm.2017.04.041_bib16) 2004; 24 Chang (10.1016/j.neuropharm.2017.04.041_bib4) 2008; 28 Coyle (10.1016/j.neuropharm.2017.04.041_bib6) 2003; 1003 Mullasseril (10.1016/j.neuropharm.2017.04.041_bib19) 2010; 1 Hu (10.1016/j.neuropharm.2017.04.041_bib11) 2005; 312 Jang (10.1016/j.neuropharm.2017.04.041_bib12) 2004; 101
References_xml	– volume: 74 start-page: 69 year: 2013 end-page: 75 ident: bib32 article-title: NMDA receptors in nervous system diseases publication-title: Neuropharmacology contributor: fullname: Sheng – volume: 417 start-page: 245 year: 2002 end-page: 253 ident: bib27 article-title: Mechanism of glutamate receptor desensitization publication-title: Nature contributor: fullname: Gouaux – volume: 59 start-page: 2760 year: 2016 Mar end-page: 2779 ident: bib29 article-title: Discovery of GluN2A-selective NMDA receptor positive allosteric modulators (PAMs): tuning deactivation kinetics via structure-based design publication-title: J. Med. Chem. contributor: fullname: Volgraf – volume: 5 start-page: 10935 year: 2015 ident: bib30 article-title: Block of NMDA receptor channels by endogenous neurosteroids: implications for the agonist induced conformational states of the channel vestibule publication-title: Sci. Rep. contributor: fullname: Vyklicky – volume: 1 start-page: 90 year: 2010 ident: bib19 article-title: A subunit-selective potentiator of NR2C- and NR2D-containing NMDA receptors publication-title: Nat. Commun. contributor: fullname: Traynelis – volume: 74 start-page: 454 year: 2008 end-page: 465 ident: bib3 article-title: The NR1 M3 domain mediates allosteric coupling in the N-methyl-D-aspartate receptor publication-title: Mol. Pharmacol. contributor: fullname: VanDongen – volume: 112 start-page: 34 year: 2017 Jan end-page: 45 ident: bib9 article-title: Diverse modes of NMDA receptor positive allosteric modulation: mechanisms and consequences publication-title: Neuropharmacology contributor: fullname: Hanson – volume: 3 start-page: 315 year: 2000 end-page: 322 ident: bib17 article-title: Mutation of a glutamate receptor motif reveals its role in gating and delta2 receptor channel properties publication-title: Nat. Neurosci. contributor: fullname: Yuzaki – volume: 129 start-page: 509 year: 2007 end-page: 525 ident: bib25 article-title: Subunit-specific contribution of pore-forming domains to NMDA receptor channel structure and gating publication-title: J. general physiol. contributor: fullname: Wollmuth – volume: 14 start-page: 383 year: 2013 end-page: 400 ident: bib23 article-title: NMDA receptor subunit diversity: impact on receptor properties, synaptic plasticity and disease publication-title: Nat. Rev. contributor: fullname: Zhou – volume: 140 start-page: 267 year: 2012 end-page: 277 ident: bib20 article-title: Probing the activation sequence of NMDA receptors with lurcher mutations publication-title: J. general physiol. contributor: fullname: Popescu – volume: 7 start-page: e27887 year: 2014 ident: bib26 article-title: Glutamate receptor mutations in psychiatric and neurodevelopmental disorders publication-title: Commun. Integr. Biol. contributor: fullname: Bayes – volume: 511 start-page: 191 year: 2014 end-page: 197 ident: bib18 article-title: NMDA receptor structures reveal subunit arrangement and pore architecture publication-title: Nature contributor: fullname: Gouaux – volume: 388 start-page: 769 year: 1997 end-page: 773 ident: bib34 article-title: Neurodegeneration in Lurcher mice caused by mutation in delta2 glutamate receptor gene publication-title: Nature contributor: fullname: Heintz – volume: 28 start-page: 1546 year: 2008 end-page: 1556 ident: bib4 article-title: The activation gate and gating mechanism of the NMDA receptor publication-title: J. Neurosci. contributor: fullname: Kuo – volume: 89 start-page: 983 year: 2016 end-page: 999 ident: bib10 article-title: Positive allosteric modulators of GluN2A-containing NMDARs with distinct modes of action and impacts on circuit function publication-title: Neuron contributor: fullname: Hanson – volume: 48 start-page: 279 year: 2005 end-page: 288 ident: bib1 article-title: Molecular mechanism of AMPA receptor noncompetitive antagonism publication-title: Neuron contributor: fullname: Stern-Bach – volume: 83 start-page: 1045 year: 2013 end-page: 1056 ident: bib22 article-title: Contribution of the M1 transmembrane helix and pre-M1 region to positive allosteric modulation and gating of N-methyl-D-aspartate receptors publication-title: Mol. Pharmacol. contributor: fullname: Traynelis – volume: 27 start-page: 12230 year: 2007 end-page: 12241 ident: bib24 article-title: A domain linking the AMPA receptor agonist binding site to the ion pore controls gating and causes lurcher properties when mutated publication-title: J. Neurosci. contributor: fullname: Hollmann – volume: 20 start-page: 14 year: 2015 end-page: 23 ident: bib33 article-title: Allosteric modulators of NMDA receptors: multiple sites and mechanisms publication-title: Curr. Opin. Pharmacol. contributor: fullname: Paoletti – volume: 25 start-page: 9027 year: 2005 end-page: 9036 ident: bib13 article-title: Mechanism of positive allosteric modulators acting on AMPA receptors publication-title: J. Neurosci. contributor: fullname: Partin – volume: 61 start-page: 533 year: 2002 end-page: 545 ident: bib15 article-title: Channel blockers acting at N-methyl-D-aspartate receptors: differential effects of mutations in the vestibule and ion channel pore publication-title: Mol. Pharmacol. contributor: fullname: Williams – volume: 344 start-page: 992 year: 2014 end-page: 997 ident: bib14 article-title: Crystal structure of a heterotetrameric NMDA receptor ion channel publication-title: Sci. (New York, N. Y. contributor: fullname: Furukawa – volume: 38 start-page: 950 year: 2012 end-page: 957 ident: bib8 article-title: NMDA receptor hypofunction, parvalbumin-positive neurons, and cortical gamma oscillations in schizophrenia publication-title: Schizophr. Bull. contributor: fullname: Lewis – volume: 312 start-page: 899 year: 2005 end-page: 904 ident: bib11 article-title: Differential effects on current kinetics by point mutations in the lurcher motif of NR1/NR2A receptors publication-title: J. Pharmacol. Exp. Ther. contributor: fullname: Zheng – volume: 62 start-page: 405 year: 2010 end-page: 496 ident: bib28 article-title: Glutamate receptor ion channels: structure, regulation, and function publication-title: Pharmacol. Rev. contributor: fullname: Dingledine – volume: 483 start-page: 367 year: 1995 end-page: 384 ident: bib2 article-title: Trapping of glutamate and glycine during open channel block of rat hippocampal neuron NMDA receptors by 9-aminoacridine publication-title: J. physiol. contributor: fullname: Mayer – volume: 345 start-page: 1021 year: 2014 end-page: 1026 ident: bib5 article-title: X-ray structures of AMPA receptor-cone snail toxin complexes illuminate activation mechanism publication-title: Sci. (New York, N. Y. contributor: fullname: Gouaux – volume: 91 start-page: 1305 year: 2016 end-page: 1315 ident: bib31 article-title: Structural bases of noncompetitive inhibition of AMPA-subtype ionotropic glutamate receptors by antiepileptic drugs publication-title: Neuron contributor: fullname: Sobolevsky – volume: 1003 start-page: 318 year: 2003 end-page: 327 ident: bib6 article-title: Converging evidence of NMDA receptor hypofunction in the pathophysiology of schizophrenia publication-title: Ann. N. Y. Acad. Sci. contributor: fullname: Goff – volume: 101 start-page: 8198 year: 2004 end-page: 8203 ident: bib12 article-title: A steroid modulatory domain on NR2B controls N-methyl-D-aspartate receptor proton sensitivity publication-title: Proc. Natl. Acad. Sci. U. S. A. contributor: fullname: Farb – volume: 24 start-page: 4941 year: 2004 end-page: 4951 ident: bib16 article-title: Effects of the lurcher mutation on GluR1 desensitization and activation kinetics publication-title: J. Neurosci. contributor: fullname: Howe – volume: 51 start-page: 7 year: 1999 end-page: 61 ident: bib7 article-title: The glutamate receptor ion channels publication-title: Pharmacol. Rev. contributor: fullname: Traynelis – volume: 74 start-page: 454 year: 2008 ident: 10.1016/j.neuropharm.2017.04.041_bib3 article-title: The NR1 M3 domain mediates allosteric coupling in the N-methyl-D-aspartate receptor publication-title: Mol. Pharmacol. doi: 10.1124/mol.107.044115 contributor: fullname: Blanke – volume: 38 start-page: 950 year: 2012 ident: 10.1016/j.neuropharm.2017.04.041_bib8 article-title: NMDA receptor hypofunction, parvalbumin-positive neurons, and cortical gamma oscillations in schizophrenia publication-title: Schizophr. Bull. doi: 10.1093/schbul/sbs010 contributor: fullname: Gonzalez-Burgos – volume: 511 start-page: 191 year: 2014 ident: 10.1016/j.neuropharm.2017.04.041_bib18 article-title: NMDA receptor structures reveal subunit arrangement and pore architecture publication-title: Nature doi: 10.1038/nature13548 contributor: fullname: Lee – volume: 112 start-page: 34 issue: Pt A year: 2017 ident: 10.1016/j.neuropharm.2017.04.041_bib9 article-title: Diverse modes of NMDA receptor positive allosteric modulation: mechanisms and consequences publication-title: Neuropharmacology doi: 10.1016/j.neuropharm.2016.07.037 contributor: fullname: Hackos – volume: 14 start-page: 383 year: 2013 ident: 10.1016/j.neuropharm.2017.04.041_bib23 article-title: NMDA receptor subunit diversity: impact on receptor properties, synaptic plasticity and disease publication-title: Nat. Rev. doi: 10.1038/nrn3504 contributor: fullname: Paoletti – volume: 312 start-page: 899 year: 2005 ident: 10.1016/j.neuropharm.2017.04.041_bib11 article-title: Differential effects on current kinetics by point mutations in the lurcher motif of NR1/NR2A receptors publication-title: J. Pharmacol. Exp. Ther. doi: 10.1124/jpet.104.077388 contributor: fullname: Hu – volume: 101 start-page: 8198 year: 2004 ident: 10.1016/j.neuropharm.2017.04.041_bib12 article-title: A steroid modulatory domain on NR2B controls N-methyl-D-aspartate receptor proton sensitivity publication-title: Proc. Natl. Acad. Sci. U. S. A. doi: 10.1073/pnas.0401838101 contributor: fullname: Jang – volume: 20 start-page: 14 year: 2015 ident: 10.1016/j.neuropharm.2017.04.041_bib33 article-title: Allosteric modulators of NMDA receptors: multiple sites and mechanisms publication-title: Curr. Opin. Pharmacol. doi: 10.1016/j.coph.2014.10.009 contributor: fullname: Zhu – volume: 27 start-page: 12230 year: 2007 ident: 10.1016/j.neuropharm.2017.04.041_bib24 article-title: A domain linking the AMPA receptor agonist binding site to the ion pore controls gating and causes lurcher properties when mutated publication-title: J. Neurosci. doi: 10.1523/JNEUROSCI.3175-07.2007 contributor: fullname: Schmid – volume: 51 start-page: 7 year: 1999 ident: 10.1016/j.neuropharm.2017.04.041_bib7 article-title: The glutamate receptor ion channels publication-title: Pharmacol. Rev. contributor: fullname: Dingledine – volume: 140 start-page: 267 year: 2012 ident: 10.1016/j.neuropharm.2017.04.041_bib20 article-title: Probing the activation sequence of NMDA receptors with lurcher mutations publication-title: J. general physiol. doi: 10.1085/jgp.201210786 contributor: fullname: Murthy – volume: 417 start-page: 245 year: 2002 ident: 10.1016/j.neuropharm.2017.04.041_bib27 article-title: Mechanism of glutamate receptor desensitization publication-title: Nature doi: 10.1038/417245a contributor: fullname: Sun – volume: 7 start-page: e27887 year: 2014 ident: 10.1016/j.neuropharm.2017.04.041_bib26 article-title: Glutamate receptor mutations in psychiatric and neurodevelopmental disorders publication-title: Commun. Integr. Biol. doi: 10.4161/cib.27887 contributor: fullname: Soto – volume: 48 start-page: 279 year: 2005 ident: 10.1016/j.neuropharm.2017.04.041_bib1 article-title: Molecular mechanism of AMPA receptor noncompetitive antagonism publication-title: Neuron doi: 10.1016/j.neuron.2005.09.024 contributor: fullname: Balannik – volume: 28 start-page: 1546 year: 2008 ident: 10.1016/j.neuropharm.2017.04.041_bib4 article-title: The activation gate and gating mechanism of the NMDA receptor publication-title: J. Neurosci. doi: 10.1523/JNEUROSCI.3485-07.2008 contributor: fullname: Chang – volume: 62 start-page: 405 year: 2010 ident: 10.1016/j.neuropharm.2017.04.041_bib28 article-title: Glutamate receptor ion channels: structure, regulation, and function publication-title: Pharmacol. Rev. doi: 10.1124/pr.109.002451 contributor: fullname: Traynelis – volume: 89 start-page: 983 year: 2016 ident: 10.1016/j.neuropharm.2017.04.041_bib10 article-title: Positive allosteric modulators of GluN2A-containing NMDARs with distinct modes of action and impacts on circuit function publication-title: Neuron doi: 10.1016/j.neuron.2016.01.016 contributor: fullname: Hackos – volume: 24 start-page: 4941 year: 2004 ident: 10.1016/j.neuropharm.2017.04.041_bib16 article-title: Effects of the lurcher mutation on GluR1 desensitization and activation kinetics publication-title: J. Neurosci. doi: 10.1523/JNEUROSCI.0660-04.2004 contributor: fullname: Klein – volume: 1 start-page: 90 year: 2010 ident: 10.1016/j.neuropharm.2017.04.041_bib19 article-title: A subunit-selective potentiator of NR2C- and NR2D-containing NMDA receptors publication-title: Nat. Commun. doi: 10.1038/ncomms1085 contributor: fullname: Mullasseril – volume: 5 start-page: 10935 year: 2015 ident: 10.1016/j.neuropharm.2017.04.041_bib30 article-title: Block of NMDA receptor channels by endogenous neurosteroids: implications for the agonist induced conformational states of the channel vestibule publication-title: Sci. Rep. doi: 10.1038/srep10935 contributor: fullname: Vyklicky – volume: 1003 start-page: 318 year: 2003 ident: 10.1016/j.neuropharm.2017.04.041_bib6 article-title: Converging evidence of NMDA receptor hypofunction in the pathophysiology of schizophrenia publication-title: Ann. N. Y. Acad. Sci. doi: 10.1196/annals.1300.020 contributor: fullname: Coyle – volume: 91 start-page: 1305 year: 2016 ident: 10.1016/j.neuropharm.2017.04.041_bib31 article-title: Structural bases of noncompetitive inhibition of AMPA-subtype ionotropic glutamate receptors by antiepileptic drugs publication-title: Neuron doi: 10.1016/j.neuron.2016.08.012 contributor: fullname: Yelshanskaya – volume: 25 start-page: 9027 year: 2005 ident: 10.1016/j.neuropharm.2017.04.041_bib13 article-title: Mechanism of positive allosteric modulators acting on AMPA receptors publication-title: J. Neurosci. doi: 10.1523/JNEUROSCI.2567-05.2005 contributor: fullname: Jin – volume: 83 start-page: 1045 year: 2013 ident: 10.1016/j.neuropharm.2017.04.041_bib22 article-title: Contribution of the M1 transmembrane helix and pre-M1 region to positive allosteric modulation and gating of N-methyl-D-aspartate receptors publication-title: Mol. Pharmacol. doi: 10.1124/mol.113.085209 contributor: fullname: Ogden – volume: 74 start-page: 69 year: 2013 ident: 10.1016/j.neuropharm.2017.04.041_bib32 article-title: NMDA receptors in nervous system diseases publication-title: Neuropharmacology doi: 10.1016/j.neuropharm.2013.03.030 contributor: fullname: Zhou – volume: 345 start-page: 1021 year: 2014 ident: 10.1016/j.neuropharm.2017.04.041_bib5 article-title: X-ray structures of AMPA receptor-cone snail toxin complexes illuminate activation mechanism publication-title: Sci. (New York, N. Y. doi: 10.1126/science.1258409 contributor: fullname: Chen – volume: 129 start-page: 509 year: 2007 ident: 10.1016/j.neuropharm.2017.04.041_bib25 article-title: Subunit-specific contribution of pore-forming domains to NMDA receptor channel structure and gating publication-title: J. general physiol. doi: 10.1085/jgp.200609718 contributor: fullname: Sobolevsky – volume: 483 start-page: 367 issue: Pt 2 year: 1995 ident: 10.1016/j.neuropharm.2017.04.041_bib2 article-title: Trapping of glutamate and glycine during open channel block of rat hippocampal neuron NMDA receptors by 9-aminoacridine publication-title: J. physiol. doi: 10.1113/jphysiol.1995.sp020591 contributor: fullname: Benveniste – volume: 61 start-page: 533 year: 2002 ident: 10.1016/j.neuropharm.2017.04.041_bib15 article-title: Channel blockers acting at N-methyl-D-aspartate receptors: differential effects of mutations in the vestibule and ion channel pore publication-title: Mol. Pharmacol. doi: 10.1124/mol.61.3.533 contributor: fullname: Kashiwagi – volume: 344 start-page: 992 year: 2014 ident: 10.1016/j.neuropharm.2017.04.041_bib14 article-title: Crystal structure of a heterotetrameric NMDA receptor ion channel publication-title: Sci. (New York, N. Y. doi: 10.1126/science.1251915 contributor: fullname: Karakas – volume: 59 start-page: 2760 issue: 6 year: 2016 ident: 10.1016/j.neuropharm.2017.04.041_bib29 article-title: Discovery of GluN2A-selective NMDA receptor positive allosteric modulators (PAMs): tuning deactivation kinetics via structure-based design publication-title: J. Med. Chem. doi: 10.1021/acs.jmedchem.5b02010 contributor: fullname: Volgraf – volume: 3 start-page: 315 year: 2000 ident: 10.1016/j.neuropharm.2017.04.041_bib17 article-title: Mutation of a glutamate receptor motif reveals its role in gating and delta2 receptor channel properties publication-title: Nat. Neurosci. doi: 10.1038/73877 contributor: fullname: Kohda – volume: 388 start-page: 769 year: 1997 ident: 10.1016/j.neuropharm.2017.04.041_bib34 article-title: Neurodegeneration in Lurcher mice caused by mutation in delta2 glutamate receptor gene publication-title: Nature doi: 10.1038/42009 contributor: fullname: Zuo
SSID	ssj0004818
Score	2.409852
Snippet	Ionotropic glutamate receptors (iGluRs) mediate fast excitatory neurotransmission and are key nervous system drug targets. While diverse pharmacological tools...
SourceID	crossref pubmed elsevier
SourceType	Aggregation Database Index Database Publisher
StartPage	204
SubjectTerms	Allosteric Regulation - drug effects Allosteric Regulation - genetics Binding Sites - drug effects Binding Sites - genetics Calcium - metabolism Dose-Response Relationship, Drug Doxycycline - pharmacology Electric Stimulation Excitatory Amino Acid Agents - chemistry Excitatory Amino Acid Agents - pharmacology Glutamic Acid - pharmacology Glycine - metabolism HEK293 Cells Humans Membrane Potentials - drug effects Membrane Potentials - genetics NMDA receptor Patch-Clamp Techniques Positive allosteric modulator Protein Domains - drug effects Protein Domains - genetics Pyrimidinones - chemistry Pyrimidinones - pharmacology Receptors, N-Methyl-D-Aspartate - genetics Receptors, N-Methyl-D-Aspartate - metabolism Sulfonamides - chemistry Sulfonamides - pharmacology Synaptic Transmission - drug effects Synaptic Transmission - genetics Synaptic Transmission - physiology Transfection Transmembrane domain
Title	A novel NMDA receptor positive allosteric modulator that acts via the transmembrane domain
URI	https://dx.doi.org/10.1016/j.neuropharm.2017.04.041 https://www.ncbi.nlm.nih.gov/pubmed/28457974
Volume	121
hasFullText	1
inHoldings	1
isFullTextHit
isPrint
link	http://utb.summon.serialssolutions.com/2.0.0/link/0/eLvHCXMwpV3NT8IwFG8QLl6M3-IH6cFwYsq2bt3iiaAENRAOkBAvS0vbOCODyCTh4t_ue2wTPWlisku3dB-_vbxfX_ver4RcBkADnDVdy2jDLKZ8acGoNbS044PP1EaHa9nFXt_vjtjD2BuXSLuohcG0ytz3Zz597a3zM9c5mtfzOMYaX6DGECgNjTTEMqsK0BGu1VZa94_d_qY8MrCDQowZO-QJPVma11o2co4y0Zjnxde6p8z-haW-UVBnl-zkY0fayl5vj5R0sk_qg0x8etWgw00t1aJB63SwkaVeHZCnFk1mS_1K-73bFoWP1nOIt2mWtbXUFFfgUTUhntDpTOGuXnA1fRYpFZN0QZexgJamKZLbVE8hyk40VbOpiJNDMurcDdtdK99ZwZowh6UWD-REN0Oc_1RMcmUAIu4YKRzUH5NC-kqKgKPvU1wK1xGhwz2pDRdeUwW-e0TKySzRJ4QG0hWCawh0Tch8ZYRyja8C1-WovCZNldgFktE8E9CIisyyl2iDfoToR00Gh10lNwXk0Q9jiMDP_6H3cfaXvp4HFOxxMMHTf933jGxjCyd2be-clNO3d30BI5JU1sjW1Yddy-3uE7Dk4z4
link.rule.ids	314,780,784,4502,24116,27924,27925,45585,45679
linkProvider	Elsevier
linkToHtml	http://utb.summon.serialssolutions.com/2.0.0/link/0/eLvHCXMwpV07T8MwELaqMsCCeFOeHhATgTycOBFTBVQF2oqhSIglsmNbBNG0oqESC7-duzwoTCAhZUmcxMnldN_Z-e4zIUchwABntmcZbZjFVCAtyFojS7sBxExtdFTILvYHQfee3Tz4Dw1yUdfCIK2yiv1lTC-idXXkrLLm2SRNscYXoDECSEMnjbDMaoH5kP2CU59-zHkeLHTCWooZT6_oPCXJqxCNnKBINLK8eKF6ypxfMOobAHVWyHKVOdJ2-XCrpKGzNXJ8V0pPv5_Q4bySanpCj-ndXJT6fZ08tmk2nukXOuhftim8sp7AaJuWnK2Zpvj_HTUT0oSOxgrX9ILW_EnkVCT5lM5SAXua5ghtIz2CMXamqRqPRJptkPvO1fCia1XrKlgJc1lu8VAm2o5w9lMxyZUBE3HXSOGi-pgUMlBShBwjn-JSeK6IXO5LbbjwbRUG3iZpZuNMbxMaSk8IrmGYayIWKCOUZwIVeh5H3TVpWsSpLRlPSvmMuOaVPcdz68do_dhmsDktcl6bPP7hCjFE-T9cvVV-pa_-AIB9Dg6486_7HpLF7rDfi3vXg9tdsoQtOMXr-Hukmb--6X3ITXJ5UPjeJ8QU5Bc
openUrl	ctx_ver=Z39.88-2004&ctx_enc=info%3Aofi%2Fenc%3AUTF-8&rfr_id=info%3Asid%2Fsummon.serialssolutions.com&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=A+novel+NMDA+receptor+positive+allosteric+modulator+that+acts+via+the+transmembrane+domain&rft.jtitle=Neuropharmacology&rft.au=Wang%2C+Tzu-Ming&rft.au=Brown%2C+Brandon+M&rft.au=Deng%2C+Lunbin&rft.au=Sellers%2C+Benjamin+D&rft.date=2017-07-15&rft.eissn=1873-7064&rft.volume=121&rft.spage=204&rft_id=info:doi/10.1016%2Fj.neuropharm.2017.04.041&rft_id=info%3Apmid%2F28457974&rft.externalDocID=28457974
thumbnail_l	http://covers-cdn.summon.serialssolutions.com/index.aspx?isbn=/lc.gif&issn=0028-3908&client=summon
thumbnail_m	http://covers-cdn.summon.serialssolutions.com/index.aspx?isbn=/mc.gif&issn=0028-3908&client=summon
thumbnail_s	http://covers-cdn.summon.serialssolutions.com/index.aspx?isbn=/sc.gif&issn=0028-3908&client=summon