{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T20:19:01Z","timestamp":1788380341008,"version":"build-2803163510"},"reference-count":53,"publisher":"Rockefeller University Press","issue":"2","license":[{"start":{"date-parts":[[2019,1,8]],"date-time":"2019-01-08T00:00:00Z","timestamp":1546905600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/www.rupress.org\/terms\/"},{"start":{"date-parts":[[2019,8,5]],"date-time":"2019-08-05T00:00:00Z","timestamp":1564963200000},"content-version":"vor","delay-in-days":209,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-sa\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01 NS085239"],"award-info":[{"award-number":["R01 NS085239"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["rupress.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2019,2,4]]},"abstract":"<jats:p>Glutamate is released from presynaptic nerve terminals in the central nervous system (CNS) and spreads excitation by binding to and activating postsynaptic iGluRs. Of the potential glutamate targets, tetrameric AMPA receptors mediate fast, transient CNS signaling. Each of the four AMPA subunits in the receptor channel complex is capable of binding glutamate at its ligand-binding domains and transmitting the energy of activation to the pore domain. Homotetrameric AMPA receptor channels open in a stepwise manner, consistent with independent activation of individual subunits, and they exhibit complex kinetic behavior that manifests as temporal shifts between four different conductance levels. Here, we investigate how two AMPA receptor-selective noncompetitive antagonists, GYKI-52466 and GYKI-53655, disrupt the intrinsic step-like gating patterns of maximally activated homotetrameric GluA3 receptors using single-channel recordings from cell-attached patches. Interactions of these 2,3-benzodiazepines with residues in the boundary between the extracellular linkers and transmembrane helical domains reorganize the gating behavior of channels. Low concentrations of modulators stabilize open and closed states to different degrees and coordinate the activation of subunits so that channels open directly from closed to higher conductance levels. Using kinetic and structural models, we provide insight into how the altered gating patterns might arise from molecular contacts within the extracellular linker-channel boundary. Our results suggest that this region may be a tunable locus for AMPA receptor channel gating.<\/jats:p>","DOI":"10.1085\/jgp.201812209","type":"journal-article","created":{"date-parts":[[2019,1,8]],"date-time":"2019-01-08T19:46:08Z","timestamp":1546976768000},"page":"156-173","update-policy":"https:\/\/doi.org\/10.1085\/jgp.crossmarkpolicy","source":"Crossref","is-referenced-by-count":21,"title":["Noncompetitive antagonists induce cooperative AMPA receptor channel gating"],"prefix":"10.1085","volume":"151","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2002-0565","authenticated-orcid":true,"given":"Edward Y.","family":"Shi","sequence":"first","affiliation":[{"name":"Department of Molecular Medicine, Cornell University, Ithaca, NY"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christine L.","family":"Yuan","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine, Cornell University, Ithaca, NY"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3194-2661","authenticated-orcid":true,"given":"Matthew T.","family":"Sipple","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine, Cornell University, Ithaca, NY"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jayasri","family":"Srinivasan","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine, Cornell University, Ithaca, NY"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2752-0367","authenticated-orcid":true,"given":"Christopher P.","family":"Ptak","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine, Cornell University, Ithaca, NY"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert E.","family":"Oswald","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine, Cornell University, Ithaca, NY"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2249-4905","authenticated-orcid":true,"given":"Linda M.","family":"Nowak","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine, Cornell University, Ithaca, NY"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"291","published-online":{"date-parts":[[2019,1,8]]},"reference":[{"key":"2023072705362123200_bib1","doi-asserted-by":"publisher","first-page":"2617","DOI":"10.1523\/JNEUROSCI.2667-15.2016","article-title":"A Molecular Determinant of Subtype-Specific Desensitization in Ionotropic Glutamate Receptors","volume":"36","author":"Alsaloum","year":"2016","journal-title":"J. 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