Non-blocking modulation contributes to sodium channel inhibition by a covalently attached photoreactive riluzole analog

Abstract Sodium channel inhibitor drugs decrease pathological hyperactivity in various diseases including pain syndromes, myotonia, arrhythmias, nerve injuries and epilepsies. Inhibiting pathological but not physiological activity, however, is a major challenge in drug development. Sodium channel in...

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Autores principales:	Peter Lukacs, Mátyás C. Földi, Luca Valánszki, Emilio Casanova, Beáta Biri-Kovács, László Nyitray, András Málnási-Csizmadia, Arpad Mike
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2018
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/f48d2435c9aa4403b15cfc5aca00707f
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spelling	oai:doaj.org-article:f48d2435c9aa4403b15cfc5aca00707f2021-12-02T15:07:44ZNon-blocking modulation contributes to sodium channel inhibition by a covalently attached photoreactive riluzole analog10.1038/s41598-018-26444-y2045-2322https://doaj.org/article/f48d2435c9aa4403b15cfc5aca00707f2018-05-01T00:00:00Zhttps://doi.org/10.1038/s41598-018-26444-yhttps://doaj.org/toc/2045-2322Abstract Sodium channel inhibitor drugs decrease pathological hyperactivity in various diseases including pain syndromes, myotonia, arrhythmias, nerve injuries and epilepsies. Inhibiting pathological but not physiological activity, however, is a major challenge in drug development. Sodium channel inhibitors exert their effects by a dual action: they obstruct ion flow (“block”), and they alter the energetics of channel opening and closing (“modulation”). Ideal drugs would be modulators without blocking effect, because modulation is inherently activity-dependent, therefore selective for pathological hyperactivity. Can block and modulation be separated? It has been difficult to tell, because the effect of modulation is obscured by conformation-dependent association/dissociation of the drug. To eliminate dynamic association/dissociation, we used a photoreactive riluzole analog which could be covalently bound to the channel; and found, unexpectedly, that drug-bound channels could still conduct ions, although with modulated gating. The finding that non-blocking modulation is possible, may open a novel avenue for drug development because non-blocking modulators could be more specific in treating hyperactivity-linked diseases.Peter LukacsMátyás C. FöldiLuca ValánszkiEmilio CasanovaBeáta Biri-KovácsLászló NyitrayAndrás Málnási-CsizmadiaArpad MikeNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 8, Iss 1, Pp 1-11 (2018)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Peter Lukacs Mátyás C. Földi Luca Valánszki Emilio Casanova Beáta Biri-Kovács László Nyitray András Málnási-Csizmadia Arpad Mike Non-blocking modulation contributes to sodium channel inhibition by a covalently attached photoreactive riluzole analog
description	Abstract Sodium channel inhibitor drugs decrease pathological hyperactivity in various diseases including pain syndromes, myotonia, arrhythmias, nerve injuries and epilepsies. Inhibiting pathological but not physiological activity, however, is a major challenge in drug development. Sodium channel inhibitors exert their effects by a dual action: they obstruct ion flow (“block”), and they alter the energetics of channel opening and closing (“modulation”). Ideal drugs would be modulators without blocking effect, because modulation is inherently activity-dependent, therefore selective for pathological hyperactivity. Can block and modulation be separated? It has been difficult to tell, because the effect of modulation is obscured by conformation-dependent association/dissociation of the drug. To eliminate dynamic association/dissociation, we used a photoreactive riluzole analog which could be covalently bound to the channel; and found, unexpectedly, that drug-bound channels could still conduct ions, although with modulated gating. The finding that non-blocking modulation is possible, may open a novel avenue for drug development because non-blocking modulators could be more specific in treating hyperactivity-linked diseases.
format	article
author	Peter Lukacs Mátyás C. Földi Luca Valánszki Emilio Casanova Beáta Biri-Kovács László Nyitray András Málnási-Csizmadia Arpad Mike
author_facet	Peter Lukacs Mátyás C. Földi Luca Valánszki Emilio Casanova Beáta Biri-Kovács László Nyitray András Málnási-Csizmadia Arpad Mike
author_sort	Peter Lukacs
title	Non-blocking modulation contributes to sodium channel inhibition by a covalently attached photoreactive riluzole analog
title_short	Non-blocking modulation contributes to sodium channel inhibition by a covalently attached photoreactive riluzole analog
title_full	Non-blocking modulation contributes to sodium channel inhibition by a covalently attached photoreactive riluzole analog
title_fullStr	Non-blocking modulation contributes to sodium channel inhibition by a covalently attached photoreactive riluzole analog
title_full_unstemmed	Non-blocking modulation contributes to sodium channel inhibition by a covalently attached photoreactive riluzole analog
title_sort	non-blocking modulation contributes to sodium channel inhibition by a covalently attached photoreactive riluzole analog
publisher	Nature Portfolio
publishDate	2018
url	https://doaj.org/article/f48d2435c9aa4403b15cfc5aca00707f
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Non-blocking modulation contributes to sodium channel inhibition by a covalently attached photoreactive riluzole analog

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