{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,2,21]],"date-time":"2025-02-21T14:04:42Z","timestamp":1740146682796,"version":"3.37.3"},"reference-count":58,"publisher":"Public Library of Science (PLoS)","issue":"3","license":[{"start":{"date-parts":[[2021,3,3]],"date-time":"2021-03-03T00:00:00Z","timestamp":1614729600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100009797","name":"Barrow Neurological Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100009797","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000009","name":"Foundation for the National Institutes of Health","doi-asserted-by":"publisher","award":["2P20GM103395"],"award-info":[{"award-number":["2P20GM103395"]}],"id":[{"id":"10.13039\/100000009","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000009","name":"Foundation for the National Institutes of Health","doi-asserted-by":"publisher","award":["DA043567"],"award-info":[{"award-number":["DA043567"]}],"id":[{"id":"10.13039\/100000009","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:p>Sleep-related hypermotor epilepsy (SHE) is a group of seizure disorders prominently associated with mutations in nicotinic acetylcholine receptors (nAChR). The most prevalent central nervous system nAChR subtype contains \u03b14 and \u03b22 subunits, in two ratios. (\u03b14\u03b22)<jats:sub>2<\/jats:sub>\u03b22-nAChR have high agonist sensitivity (HS-isoform), whereas (\u03b14\u03b22)<jats:sub>2<\/jats:sub>\u03b14-nAChR agonist responses exhibit a small high-sensitivity, and a predominant low-sensitivity, phase of function (LS-isoform). Multiple non-synonymous mutations in the second and third transmembrane domains of \u03b14 and \u03b22 subunits are associated with SHE. We recently demonstrated that two additional, SHE-associated, missense mutations in the major cytoplasmic loops of these subunits [\u03b14(R336H) and \u03b22(V337G)] cause increased macroscopic function-per receptor. Here, we use single-channel patch-clamp electrophysiology to show that these mutations influence single-channel amplitudes and open- and closed-state kinetics. Pure populations of HS- or LS-isoform \u03b14\u03b22-nAChR were expressed by injecting either 1:10 or 30:1 \u03b14:\u03b22 cRNA ratios, respectively, into <jats:italic>Xenopus laevis<\/jats:italic> oocytes. Functional properties of the resulting mutant \u03b14\u03b22-nAChR isoforms were compared to their wildtype counterparts. \u03b14(R336H) subunit incorporation minimally affected single-channel amplitudes, whereas \u03b22(V337G) subunit incorporation reduced them significantly in both isoforms. However, for both mutant subunits, increased function-per-receptor was predominantly caused by altered single channel kinetics. The \u03b14(R336H) mutation primarily destabilizes desensitized states between openings. By contrast, the \u03b22(V337G) mutation principally stabilizes receptor open states. The use of naturally-occurring and physiologically-impactful mutations has allowed us to define valuable new insights regarding the functional roles of nAChR intracellular domains. Further mechanistic context is provided by intracellular-domain structures recently published for other members of the Cys-loop receptor superfamily (\u03b13\u03b24-nAChR and 5-HT<jats:sub>3A<\/jats:sub>R).<\/jats:p>","DOI":"10.1371\/journal.pone.0247825","type":"journal-article","created":{"date-parts":[[2021,3,3]],"date-time":"2021-03-03T19:30:23Z","timestamp":1614799823000},"page":"e0247825","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":4,"title":["Sleep-related hypermotor epilepsy associated mutations uncover important kinetic roles of \u03b14\u03b22- nicotinic acetylcholine receptor intracellular structures"],"prefix":"10.1371","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9051-8150","authenticated-orcid":true,"given":"Maegan M.","family":"Weltzin","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andrew A.","family":"George","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ronald J.","family":"Lukas","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Paul","family":"Whiteaker","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2021,3,3]]},"reference":[{"issue":"19","key":"pone.0247825.ref001","doi-asserted-by":"crossref","first-page":"1834","DOI":"10.1212\/WNL.0000000000002666","article-title":"Definition and diagnostic criteria of sleep-related hypermotor epilepsy","volume":"86","author":"P Tinuper","year":"2016","journal-title":"Neurology"},{"issue":"8896","key":"pone.0247825.ref002","doi-asserted-by":"crossref","first-page":"515","DOI":"10.1016\/S0140-6736(94)91463-X","article-title":"Autosomal dominant frontal epilepsy misdiagnosed as sleep disorder","volume":"343","author":"IE Scheffer","year":"1994","journal-title":"Lancet"},{"issue":"2","key":"pone.0247825.ref003","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1038\/ng1095-201","article-title":"A missense mutation in the neuronal nicotinic acetylcholine receptor alpha 4 subunit is associated with autosomal dominant nocturnal frontal lobe epilepsy","volume":"11","author":"OK Steinlein","year":"1995","journal-title":"Nat Genet"},{"issue":"2","key":"pone.0247825.ref004","first-page":"397","article-title":"International Union of Pharmacology. 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