|
ИСТИНА |
Войти в систему Регистрация |
ИСТИНА ИНХС РАН |
||
Point Mutations of Nicotinic Receptor $\upalpha$1 Subunit Reveal New Molecular Features of G153S Slow-Channel Myastheniaстатья
Информация о цитировании статьи получена из
Scopus,
Web of Science
Статья опубликована в журнале из списка Web of Science и/или Scopus
Дата последнего поиска статьи во внешних источниках: 1 декабря 2021 г.
- Авторы: Kudryavtsev Denis, Isaeva Anastasia, Barkova Daria, Spirova Ekaterina, Mukhutdinova Renata, Kasheverov Igor, Tsetlin Victor
- Журнал: Molecules
- Том: 26
- Номер: 5
- Год издания: 2021
- Издательство: MDPI
- Местоположение издательства: Basel, Switzerland
- Первая страница: 1278
- DOI: 10.3390/molecules26051278
- Аннотация: Slow-channel congenital myasthenic syndromes (SCCMSs) are rare genetic diseases caused by mutations in muscle nicotinic acetylcholine receptor (nAChR) subunits. Most of the known SCCMS-associated mutations localize at the transmembrane region near the ion pore. Only two SCCMS point mutations are at the extracellular domains near the acetylcholine binding site, α1(G153S) being one of them. In this work, a combination of molecular dynamics, targeted mutagenesis, fluorescent Ca2+ imaging and patch-clamp electrophysiology has been applied to G153S mutant muscle nAChR to investigate the role of hydrogen bonds formed by Ser 153 with C-loop residues near the acetylcholine-binding site. Introduction of L199T mutation to the C-loop in the vicinity of Ser 153 changed hydrogen bonds distribution, decreased acetylcholine potency (EC50 2607 vs. 146 nM) of the double mutant and decay kinetics of acetylcholine-evoked cytoplasmic Ca2+ rise (τ 14.2 ± 0.3 vs. 34.0 ± 0.4 s). These results shed light on molecular mechanisms of nAChR activation-desensitization and on the involvement of such mechanisms in channelopathy genesis.
- Добавил в систему: Смирнова Инна Григорьевна