Direct evidence that scorpion α-toxins (site-3) modulate sodium channel inactivation by hindrance of voltage-sensor movements.

The position of the voltage-sensing transmembrane segment, S4, in voltage-gated ion channels as a function of voltage remains incompletely elucidated. Site-3 toxins bind primarily to the extracellular loops connecting transmembrane helical segments S1-S2 and S3-S4 in Domain 4 (D4) and S5-S6 in Domai...

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Autores principales:	Zhongming Ma, Jun Kong, Dalia Gordon, Michael Gurevitz, Roland G Kallen
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2013
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/6ff0ae15281c45bcacfd8359c0720ee3
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spelling	oai:doaj.org-article:6ff0ae15281c45bcacfd8359c0720ee32021-11-18T08:44:45ZDirect evidence that scorpion α-toxins (site-3) modulate sodium channel inactivation by hindrance of voltage-sensor movements.1932-620310.1371/journal.pone.0077758https://doaj.org/article/6ff0ae15281c45bcacfd8359c0720ee32013-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/24302985/pdf/?tool=EBIhttps://doaj.org/toc/1932-6203The position of the voltage-sensing transmembrane segment, S4, in voltage-gated ion channels as a function of voltage remains incompletely elucidated. Site-3 toxins bind primarily to the extracellular loops connecting transmembrane helical segments S1-S2 and S3-S4 in Domain 4 (D4) and S5-S6 in Domain 1 (D1) and slow fast-inactivation of voltage-gated sodium channels. As S4 of the human skeletal muscle voltage-gated sodium channel, hNav1.4, moves in response to depolarization from the resting to the inactivated state, two D4S4 reporters (R2C and R3C, Arg1451Cys and Arg1454Cys, respectively) move from internal to external positions as deduced by reactivity to internally or externally applied sulfhydryl group reagents, methane thiosulfonates (MTS). The changes in reporter reactivity, when cycling rapidly between hyperpolarized and depolarized voltages, enabled determination of the positions of the D4 voltage-sensor and of its rate of movement. Scorpion α-toxin binding impedes D4S4 segment movement during inactivation since the modification rates of R3C in hNav1.4 with methanethiosulfonate (CH3SO2SCH2CH2R, where R = -N(CH3)3 (+) trimethylammonium, MTSET) and benzophenone-4-carboxamidocysteine methanethiosulfonate (BPMTS) were slowed ~10-fold in toxin-modified channels. Based upon the different size, hydrophobicity and charge of the two reagents it is unlikely that the change in reactivity is due to direct or indirect blockage of access of this site to reagent in the presence of toxin (Tx), but rather is the result of inability of this segment to move outward to the normal extent and at the normal rate in the toxin-modified channel. Measurements of availability of R3C to internally applied reagent show decreased access (slower rates of thiol reaction) providing further evidence for encumbered D4S4 movement in the presence of toxins consistent with the assignment of at least part of the toxin binding site to the region of D4S4 region of the voltage-sensor module.Zhongming MaJun KongDalia GordonMichael GurevitzRoland G KallenPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 8, Iss 11, p e77758 (2013)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Zhongming Ma Jun Kong Dalia Gordon Michael Gurevitz Roland G Kallen Direct evidence that scorpion α-toxins (site-3) modulate sodium channel inactivation by hindrance of voltage-sensor movements.
description	The position of the voltage-sensing transmembrane segment, S4, in voltage-gated ion channels as a function of voltage remains incompletely elucidated. Site-3 toxins bind primarily to the extracellular loops connecting transmembrane helical segments S1-S2 and S3-S4 in Domain 4 (D4) and S5-S6 in Domain 1 (D1) and slow fast-inactivation of voltage-gated sodium channels. As S4 of the human skeletal muscle voltage-gated sodium channel, hNav1.4, moves in response to depolarization from the resting to the inactivated state, two D4S4 reporters (R2C and R3C, Arg1451Cys and Arg1454Cys, respectively) move from internal to external positions as deduced by reactivity to internally or externally applied sulfhydryl group reagents, methane thiosulfonates (MTS). The changes in reporter reactivity, when cycling rapidly between hyperpolarized and depolarized voltages, enabled determination of the positions of the D4 voltage-sensor and of its rate of movement. Scorpion α-toxin binding impedes D4S4 segment movement during inactivation since the modification rates of R3C in hNav1.4 with methanethiosulfonate (CH3SO2SCH2CH2R, where R = -N(CH3)3 (+) trimethylammonium, MTSET) and benzophenone-4-carboxamidocysteine methanethiosulfonate (BPMTS) were slowed ~10-fold in toxin-modified channels. Based upon the different size, hydrophobicity and charge of the two reagents it is unlikely that the change in reactivity is due to direct or indirect blockage of access of this site to reagent in the presence of toxin (Tx), but rather is the result of inability of this segment to move outward to the normal extent and at the normal rate in the toxin-modified channel. Measurements of availability of R3C to internally applied reagent show decreased access (slower rates of thiol reaction) providing further evidence for encumbered D4S4 movement in the presence of toxins consistent with the assignment of at least part of the toxin binding site to the region of D4S4 region of the voltage-sensor module.
format	article
author	Zhongming Ma Jun Kong Dalia Gordon Michael Gurevitz Roland G Kallen
author_facet	Zhongming Ma Jun Kong Dalia Gordon Michael Gurevitz Roland G Kallen
author_sort	Zhongming Ma
title	Direct evidence that scorpion α-toxins (site-3) modulate sodium channel inactivation by hindrance of voltage-sensor movements.
title_short	Direct evidence that scorpion α-toxins (site-3) modulate sodium channel inactivation by hindrance of voltage-sensor movements.
title_full	Direct evidence that scorpion α-toxins (site-3) modulate sodium channel inactivation by hindrance of voltage-sensor movements.
title_fullStr	Direct evidence that scorpion α-toxins (site-3) modulate sodium channel inactivation by hindrance of voltage-sensor movements.
title_full_unstemmed	Direct evidence that scorpion α-toxins (site-3) modulate sodium channel inactivation by hindrance of voltage-sensor movements.
title_sort	direct evidence that scorpion α-toxins (site-3) modulate sodium channel inactivation by hindrance of voltage-sensor movements.
publisher	Public Library of Science (PLoS)
publishDate	2013
url	https://doaj.org/article/6ff0ae15281c45bcacfd8359c0720ee3
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_version_	1718421388915638272

Direct evidence that scorpion α-toxins (site-3) modulate sodium channel inactivation by hindrance of voltage-sensor movements.

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