Mutations causing congenital myasthenia reveal principal coupling pathway in the acetylcholine receptor ?-subunit

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dc.contributor.authorShen X.-M.
dc.contributor.authorBrengman J.M.
dc.contributor.authorShen S.
dc.contributor.authorDurmus H.
dc.contributor.authorPreethish-Kumar V.
dc.contributor.authorYuceyar N.
dc.contributor.authorVengalil S.
dc.contributor.authorNalini A.
dc.contributor.authorDeymeer F.
dc.contributor.authorSine S.M.
dc.contributor.authorEngel A.G.
dc.date.accessioned2019-10-27T08:02:23Z
dc.date.available2019-10-27T08:02:23Z
dc.date.issued2018
dc.departmentEge Üniversitesien_US
dc.description.abstractWe identify 2 homozygous mutations in the ?-subunit of the muscle acetylcholine receptor (AChR) in 3 patients with severe congenital myasthenia: ?R218W in the pre-M1 region in 2 patients and ?E184K in the ß8-ß9 linker in 1 patient. Arg218 is conserved in all eukaryotic members of the Cys-loop receptor superfamily, while Glu184 is conserved in the ?-, ?-, and ?-subunits of AChRs from all species. ?R218W reduces channel gating efficiency 338-fold and AChR expression on the cell surface 5-fold, whereas ?E184K reduces channel gating efficiency 11-fold but does not alter AChR cell surface expression. Determinations of the effective channel gating rate constants, combined with mutant cycle analyses, demonstrate strong energetic coupling between ?R218 and ?E184, and between ?R218 and ?E45 from the ß1-ß2 linker, as also observed for equivalent residues in the principal coupling pathway of the ?-subunit. Thus, efficient and rapid gating of the AChR channel is achieved not only by coupling between conserved residues within the principal coupling pathway of the ?-subunit, but also between corresponding residues in the ?-subunit.en_US
dc.identifier.doi10.1172/jci.insight.97826en_US
dc.identifier.issn2379-3708
dc.identifier.issue2en_US
dc.identifier.pmid29367459en_US
dc.identifier.scopusqualityQ1en_US
dc.identifier.urihttps://doi.org/10.1172/jci.insight.97826
dc.identifier.urihttps://hdl.handle.net/11454/25175
dc.identifier.volume3en_US
dc.indekslendigikaynakScopusen_US
dc.indekslendigikaynakPubMeden_US
dc.language.isoenen_US
dc.publisherNLM (Medline)en_US
dc.relation.ispartofJCI insighten_US
dc.relation.publicationcategoryMakale - Uluslararası Hakemli Dergi - Kurum Öğretim Elemanıen_US
dc.rightsinfo:eu-repo/semantics/openAccessen_US
dc.subjectIon channelsen_US
dc.subjectMuscle Biologyen_US
dc.subjectNeuromuscular diseaseen_US
dc.subjectNeuroscienceen_US
dc.subjectSignal transductionen_US
dc.titleMutations causing congenital myasthenia reveal principal coupling pathway in the acetylcholine receptor ?-subuniten_US
dc.typeArticleen_US

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