Point Mutations of Nicotinic Receptor α1 Subunit Reveal New Molecular Features of G153S Slow-Channel Myasthenia

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...
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Gespeichert in:

Autor*in:	Denis Kudryavtsev [verfasserIn] Anastasia Isaeva [verfasserIn] Daria Barkova [verfasserIn] Ekaterina Spirova [verfasserIn] Renata Mukhutdinova [verfasserIn] Igor Kasheverov [verfasserIn] Victor Tsetlin [verfasserIn]

Format:	E-Artikel
Sprache:	Englisch

Erschienen:	2021

Schlagwörter:	muscle nicotinic receptor gain-of-function channelopathy slow-channel congenital myasthenia patch-clamp molecular dynamics

Übergeordnetes Werk:	In: Molecules - MDPI AG, 2003, 26(2021), 5, p 1278
Übergeordnetes Werk:	volume:26 ; year:2021 ; number:5, p 1278

Links:	Link aufrufen Link aufrufen Link aufrufen Journal toc

DOI / URN:	10.3390/molecules26051278

Katalog-ID:	DOAJ054443431

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520			\|a 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 Ca<sup<2+</sup< 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 (EC<sub<50</sub< 2607 vs. 146 nM) of the double mutant and decay kinetics of acetylcholine-evoked cytoplasmic Ca<sup<2+</sup< 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.
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callnumber-first	Q - Science
author	Denis Kudryavtsev
spellingShingle	Denis Kudryavtsev misc QD241-441 misc muscle nicotinic receptor misc gain-of-function misc channelopathy misc slow-channel congenital myasthenia misc patch-clamp misc molecular dynamics misc Organic chemistry Point Mutations of Nicotinic Receptor α1 Subunit Reveal New Molecular Features of G153S Slow-Channel Myasthenia
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topic_title	QD241-441 Point Mutations of Nicotinic Receptor α1 Subunit Reveal New Molecular Features of G153S Slow-Channel Myasthenia muscle nicotinic receptor gain-of-function channelopathy slow-channel congenital myasthenia patch-clamp molecular dynamics
topic	misc QD241-441 misc muscle nicotinic receptor misc gain-of-function misc channelopathy misc slow-channel congenital myasthenia misc patch-clamp misc molecular dynamics misc Organic chemistry
topic_unstemmed	misc QD241-441 misc muscle nicotinic receptor misc gain-of-function misc channelopathy misc slow-channel congenital myasthenia misc patch-clamp misc molecular dynamics misc Organic chemistry
topic_browse	misc QD241-441 misc muscle nicotinic receptor misc gain-of-function misc channelopathy misc slow-channel congenital myasthenia misc patch-clamp misc molecular dynamics misc Organic chemistry
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title	Point Mutations of Nicotinic Receptor α1 Subunit Reveal New Molecular Features of G153S Slow-Channel Myasthenia
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title_full	Point Mutations of Nicotinic Receptor α1 Subunit Reveal New Molecular Features of G153S Slow-Channel Myasthenia
author_sort	Denis Kudryavtsev
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author_browse	Denis Kudryavtsev Anastasia Isaeva Daria Barkova Ekaterina Spirova Renata Mukhutdinova Igor Kasheverov Victor Tsetlin
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title_sort	point mutations of nicotinic receptor α1 subunit reveal new molecular features of g153s slow-channel myasthenia
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title_auth	Point Mutations of Nicotinic Receptor α1 Subunit Reveal New Molecular Features of G153S Slow-Channel Myasthenia
abstract	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 Ca<sup<2+</sup< 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 (EC<sub<50</sub< 2607 vs. 146 nM) of the double mutant and decay kinetics of acetylcholine-evoked cytoplasmic Ca<sup<2+</sup< 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.
abstractGer	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 Ca<sup<2+</sup< 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 (EC<sub<50</sub< 2607 vs. 146 nM) of the double mutant and decay kinetics of acetylcholine-evoked cytoplasmic Ca<sup<2+</sup< 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.
abstract_unstemmed	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 Ca<sup<2+</sup< 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 (EC<sub<50</sub< 2607 vs. 146 nM) of the double mutant and decay kinetics of acetylcholine-evoked cytoplasmic Ca<sup<2+</sup< 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.
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title_short	Point Mutations of Nicotinic Receptor α1 Subunit Reveal New Molecular Features of G153S Slow-Channel Myasthenia
url	https://doi.org/10.3390/molecules26051278 https://doaj.org/article/1883d9d82ce144528da8b6cc88ccab2a https://www.mdpi.com/1420-3049/26/5/1278 https://doaj.org/toc/1420-3049
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author2	Anastasia Isaeva Daria Barkova Ekaterina Spirova Renata Mukhutdinova Igor Kasheverov Victor Tsetlin
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up_date	2024-07-03T23:08:49.032Z
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Point Mutations of Nicotinic Receptor α1 Subunit Reveal New Molecular Features of G153S Slow-Channel Myasthenia

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