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Within the flexible linker between the agonist binding domain (ABD) and the M1 helix of the pore-forming transmembrane helical bundle lies a two-turn, extracellular pre-M1 helix positioned parallel to the plasma membrane and in van der Waals contact with the M3 helix thought to constitute the channel gate. The pre-M1 helix is tethered to the bilobed ABD, where agonist-induced conformational changes initiate activation. Additionally, it is a locus for de novo mutations associated with neurological disorders, is near other disease-associated de novo sites within the transmembrane domain, and is a structural determinant of subunit-selective modulators. To investigate the role of the pre-M1 helix in channel gating, we performed scanning mutagenesis across the GluN2A pre-M1 helix and recorded whole-cell macroscopic and single channel currents from HEK293 cell-attached patches. We identified two residues at which mutations perturb channel open probability, the mean open time, and the glutamate deactivation time course. We identified a subunit-specific network of aromatic amino acids located in and around the GluN2A pre-M1 helix to be important for gating. Based on these results, we are able to hypothesize about the role of the pre-M1 helix in other NMDAR subunits based on sequence and structure homology. Our results emphasize the role of the pre-M1 helix in channel gating, implicate the surrounding amino acid environment in this mechanism, and suggest unique subunit-specific contributions of pre-M1 helices to GluN1 and GluN2 gating.<\/jats:p>","DOI":"10.1085\/jgp.201912362","type":"journal-article","created":{"date-parts":[[2020,3,27]],"date-time":"2020-03-27T21:47:52Z","timestamp":1585345672000},"update-policy":"https:\/\/doi.org\/10.1085\/jgp.crossmarkpolicy","source":"Crossref","is-referenced-by-count":35,"title":["NMDA receptor channel gating control by the pre-M1 helix"],"prefix":"10.1085","volume":"152","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4528-7108","authenticated-orcid":true,"given":"Miranda J.","family":"McDaniel","sequence":"first","affiliation":[{"name":"Department of Pharmacology, Rollins Research Center, Emory University, Atlanta, GA 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kevin K.","family":"Ogden","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Rollins Research Center, Emory University, Atlanta, GA 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2330-2864","authenticated-orcid":true,"given":"Steven A.","family":"Kell","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Rollins Research Center, Emory University, Atlanta, GA 1"},{"name":"Department of Chemistry, Emory University, Atlanta, GA 2"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pieter B.","family":"Burger","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Emory University, Atlanta, GA 2"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dennis C.","family":"Liotta","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Emory University, Atlanta, GA 2"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3750-9615","authenticated-orcid":true,"given":"Stephen F.","family":"Traynelis","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Rollins Research Center, Emory University, Atlanta, GA 1"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"291","published-online":{"date-parts":[[2020,3,27]]},"reference":[{"key":"2023072706002349700_bib1","doi-asserted-by":"publisher","first-page":"217","DOI":"10.1038\/nature12439","article-title":"De novo mutations in epileptic encephalopathies","volume":"501","author":"Allen","year":"2013","journal-title":"Nature."},{"key":"2023072706002349700_bib2","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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