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A glutamate concentration-biased allosteric modulator potentiates NMDA-induced ion influx in neurons

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dc.contributor.authorCosta, Blaise M.en
dc.contributor.authorKwapisz, Lina Cortesen
dc.contributor.authorMehrkens, Brittneyen
dc.contributor.authorBledsoe, Douglas N.en
dc.contributor.authorVacca, Bryanna N.en
dc.contributor.authorJohnston, Tullia V.en
dc.contributor.authorRazzaq, Rehanen
dc.contributor.authorManickam, Dhanasekaranen
dc.contributor.authorKlein, Bradley G.en
dc.date.accessioned2021-12-09T20:37:52Zen
dc.date.available2021-12-09T20:37:52Zen
dc.date.issued2021-10-01en
dc.date.updated2021-12-09T20:37:48Zen
dc.description.abstractPrecisely controlled synaptic glutamate concentration is essential for the normal function of the N-methyl D-aspartate (NMDA) receptors. Atypical fluctuations in synaptic glutamate homeostasis lead to aberrant NMDA receptor activity that results in the pathogenesis of neurological and psychiatric disorders. Therefore, glutamate concentration-dependent NMDA receptor modulators would be clinically useful agents with fewer on-target adverse effects. In the present study, we have characterized a novel compound (CNS4) that potentiates NMDA receptor currents based on glutamate concentration. This compound alters glutamate potency and exhibits no voltage-dependent effect. Patch-clamp electrophysiology recordings confirmed agonist concentration-dependent changes in maximum inducible currents. Dynamic Ca2+ and Na+ imaging assays using rat brain cortical, striatal and cerebellar neurons revealed CNS4 potentiated ion influx through native NMDA receptor activity. Overall, CNS4 is novel in chemical structure, mechanism of action and agonist concentration-biased allosteric modulatory effect. This compound or its future analogs will serve as useful candidates to develop drug-like compounds for the treatment of treatment-resistant schizophrenia and major depression disorders associated with hypoglutamatergic neurotransmission.en
dc.description.versionPublished versionen
dc.format.extent14 page(s)en
dc.format.mimetypeapplication/pdfen
dc.identifierARTN e00859 (Article number)en
dc.identifier.doihttps://doi.org/10.1002/prp2.859en
dc.identifier.eissn2052-1707en
dc.identifier.issn2052-1707en
dc.identifier.issue5en
dc.identifier.orcidKlein, Bradley [0000-0003-0432-5286]en
dc.identifier.pmid34476911en
dc.identifier.urihttp://hdl.handle.net/10919/106911en
dc.identifier.volume9en
dc.language.isoenen
dc.publisherWileyen
dc.relation.urihttp://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000705449600018&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=930d57c9ac61a043676db62af60056c1en
dc.rightsCreative Commons Attribution 4.0 Internationalen
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en
dc.subjectLife Sciences & Biomedicineen
dc.subjectPharmacology & Pharmacyen
dc.subjectanti-NMDA receptor encephalopathyen
dc.subjectbiased allosteric modulator (BAM)en
dc.subjectNMDA receptoren
dc.subjectschizophreniaen
dc.subjectMETHYL-D-ASPARTATEen
dc.subjectSYNAPTICALLY RELEASED GLUTAMATEen
dc.subjectSUBUNIT COMPOSITIONen
dc.subjectRECEPTOR DIVERSITYen
dc.subjectAMINO-ACIDSen
dc.subjectEXPRESSIONen
dc.subjectFAMILYen
dc.subjectBRAINen
dc.subjectSCHIZOPHRENIAen
dc.subjectPHARMACOLOGYen
dc.subjectNMDA receptoren
dc.subject0304 Medicinal and Biomolecular Chemistryen
dc.subject1115 Pharmacology and Pharmaceutical Sciencesen
dc.titleA glutamate concentration-biased allosteric modulator potentiates NMDA-induced ion influx in neuronsen
dc.title.serialPharmacology Research & Perspectivesen
dc.typeArticle - Refereeden
dc.type.dcmitypeTexten
dc.type.otherArticleen
dc.type.otherJournalen
dcterms.dateAccepted2021-08-14en
pubs.organisational-group/Virginia Techen
pubs.organisational-group/Virginia Tech/Veterinary Medicineen
pubs.organisational-group/Virginia Tech/Veterinary Medicine/Biomedical Sciences and Pathobiologyen
pubs.organisational-group/Virginia Tech/Faculty of Health Sciencesen
pubs.organisational-group/Virginia Tech/All T&R Facultyen
pubs.organisational-group/Virginia Tech/Veterinary Medicine/CVM T&R Facultyen

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