Mutations causing congenital myasthenia reveal principal coupling pathway in the acetylcholine receptor ?-subunit
| العنوان: | Mutations causing congenital myasthenia reveal principal coupling pathway in the acetylcholine receptor ?-subunit |
|---|---|
| المؤلفون: | Joan M. Brengman, Steven M. Sine, Andrew G. Engel, Nur Yüceyar, Feza Deymeer, Atchayaram Nalini, Veeramani Preethish-Kumar, Seena Vengalil, Hacer Durmus, Xin Ming Shen, Shelley Shen |
| المساهمون: | Ege Üniversitesi |
| بيانات النشر: | NLM (Medline), 2018. |
| سنة النشر: | 2018 |
| مصطلحات موضوعية: | 0301 basic medicine, Adult, Patch-Clamp Techniques, Protein subunit, Mutant, DNA Mutational Analysis, Glutamic Acid, Gating, Receptors, Nicotinic, Signal transduction, Arginine, 03 medical and health sciences, Consanguinity, Humans, Receptor, Muscle, Skeletal, Ion channel, Acetylcholine receptor, Myasthenic Syndromes, Congenital, Chemistry, Homozygote, ComputerSystemsOrganization_COMPUTER-COMMUNICATIONNETWORKS, General Medicine, Neuromuscular disease, Evoked Potentials, Motor, Recombinant Proteins, Cell biology, Coupling (electronics), ComputingMilieux_MANAGEMENTOFCOMPUTINGANDINFORMATIONSYSTEMS, 030104 developmental biology, HEK293 Cells, ComputingMethodologies_PATTERNRECOGNITION, Ion channels, Mutation, Muscle Biology, Female, InformationSystems_MISCELLANEOUS, Research Article, Neuroscience |
| الوصف: | WOS: 000423337400011 PubMed ID: 29367459 We identify 2 homozygous mutations in the epsilon-subunit of the muscle acetylcholine receptor ( AChR) in 3 patients with severe congenital myasthenia: epsilon R218W in the pre-M1 region in 2 patients and epsilon E184K in the beta 8-beta 9 linker in 1 patient. Arg218 is conserved in all eukaryotic members of the Cysloop receptor superfamily, while Glu184 is conserved in the alpha-, delta-, and epsilon-subunits of AChRs from all species. epsilon R218W reduces channel gating efficiency 338-fold and AChR expression on the cell surface 5-fold, whereas epsilon 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 epsilon R218 and epsilon E184, and between eR218 and epsilon E45 from the beta 1-beta 2 linker, as also observed for equivalent residues in the principal coupling pathway of the alpha-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 alpha-subunit, but also between corresponding residues in the epsilon-subunit. NIH grantUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [NS 6277, NS031744] This work was supported in part by NIH grants NS 6277 to AGE and NS031744 to SMS. |
| اللغة: | English |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::e6bfeed66106882b9280142978caefa0Test https://hdl.handle.net/11454/25175Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....e6bfeed66106882b9280142978caefa0 |
| قاعدة البيانات: | OpenAIRE |
| الوصف غير متاح. |