4-Chloro-3-nitro-N-butylbenzenesulfonamide acts on KV3.1 channels by an open-channel blocker mechanism
Autor(a) principal: | |
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Data de Publicação: | 2017 |
Outros Autores: | , |
Tipo de documento: | Artigo |
Idioma: | eng |
Título da fonte: | Repositório Institucional da UNESP |
Texto Completo: | http://dx.doi.org/10.1007/s00726-017-2488-0 http://hdl.handle.net/11449/175152 |
Resumo: | The effects of 4-chloro-3-nitro-N-butylbenzenesulfonamide (SMD2) on KV3.1 channels, heterologous expressed in L-929 cells, were studied with the whole cell patch-clamp technique. SMD2 blocks KV3.1 in a reversible and use-dependent manner, with IC50 around 10 µM, and a Hill coefficient around 2. Although the conductance vs. voltage relationship in control condition can be described by a single Boltzmann function, two terms are necessary to describe the data in the presence of SMD2. The activation and deactivation time constants are weakly voltage dependent both for control and in the presence of SMD2. SMD2 does not change the channel selectivity and tail currents show a typical crossover phenomenon. The time course of inactivation has a fast and a slow component, and SMD2 significantly decreased their values. Steady-state inactivation is best described by a Boltzmann equation with V1/2 (the voltage where the probability to find the channels in the inactivated state is 50%) and K (slope factor) equals to −22.9 ± 1.5 mV and 5.3 ± 0.9 mV for control, and −30.3 ± 1.3 mV and 6 ± 0.8 mV for SMD2, respectively. The action of SMD2 is enhanced by high frequency stimulation, and by the time the channel stays open. Taken together, our results suggest that SMD2 blocks the open conformation of KV3.1. From a pharmacological and therapeutic point of view, N-alkylsulfonamides may constitute a new class of pharmacological modulators of KV3.1. |
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Repositório Institucional da UNESP |
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4-Chloro-3-nitro-N-butylbenzenesulfonamide acts on KV3.1 channels by an open-channel blocker mechanismKV3.1N-alkylbenzenesulfonamidesOpen-channel blockersPatch-clampThe effects of 4-chloro-3-nitro-N-butylbenzenesulfonamide (SMD2) on KV3.1 channels, heterologous expressed in L-929 cells, were studied with the whole cell patch-clamp technique. SMD2 blocks KV3.1 in a reversible and use-dependent manner, with IC50 around 10 µM, and a Hill coefficient around 2. Although the conductance vs. voltage relationship in control condition can be described by a single Boltzmann function, two terms are necessary to describe the data in the presence of SMD2. The activation and deactivation time constants are weakly voltage dependent both for control and in the presence of SMD2. SMD2 does not change the channel selectivity and tail currents show a typical crossover phenomenon. The time course of inactivation has a fast and a slow component, and SMD2 significantly decreased their values. Steady-state inactivation is best described by a Boltzmann equation with V1/2 (the voltage where the probability to find the channels in the inactivated state is 50%) and K (slope factor) equals to −22.9 ± 1.5 mV and 5.3 ± 0.9 mV for control, and −30.3 ± 1.3 mV and 6 ± 0.8 mV for SMD2, respectively. The action of SMD2 is enhanced by high frequency stimulation, and by the time the channel stays open. Taken together, our results suggest that SMD2 blocks the open conformation of KV3.1. From a pharmacological and therapeutic point of view, N-alkylsulfonamides may constitute a new class of pharmacological modulators of KV3.1.Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Fine Organic Chemistry Laboratory Department of Chemistry and Biochemistry Faculty of Science and Technology São Paulo State University (Unesp)-Campus of Presidente PrudentePost-Graduate Program in Science and Material TechnologyDepartment of Physiology Ribeirão Preto Medical School University of São PauloFine Organic Chemistry Laboratory Department of Chemistry and Biochemistry Faculty of Science and Technology São Paulo State University (Unesp)-Campus of Presidente PrudenteFAPESP: 12/19750-7FAPESP: 2013/24487-6Universidade Estadual Paulista (Unesp)Post-Graduate Program in Science and Material TechnologyUniversidade de São Paulo (USP)Bassetto Junior, Carlos Alberto Zanutto [UNESP]Varanda, Wamberto AntonioGonzález, Eduardo René Pérez [UNESP]2018-12-11T17:14:36Z2018-12-11T17:14:36Z2017-11-01info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/article1895-1906application/pdfhttp://dx.doi.org/10.1007/s00726-017-2488-0Amino Acids, v. 49, n. 11, p. 1895-1906, 2017.1438-21990939-4451http://hdl.handle.net/11449/17515210.1007/s00726-017-2488-02-s2.0-850291489972-s2.0-85029148997.pdfScopusreponame:Repositório Institucional da UNESPinstname:Universidade Estadual Paulista (UNESP)instacron:UNESPengAmino Acids1,1351,135info:eu-repo/semantics/openAccess2024-06-18T18:18:05Zoai:repositorio.unesp.br:11449/175152Repositório InstitucionalPUBhttp://repositorio.unesp.br/oai/requestopendoar:29462024-08-05T17:40:29.076453Repositório Institucional da UNESP - Universidade Estadual Paulista (UNESP)false |
dc.title.none.fl_str_mv |
4-Chloro-3-nitro-N-butylbenzenesulfonamide acts on KV3.1 channels by an open-channel blocker mechanism |
title |
4-Chloro-3-nitro-N-butylbenzenesulfonamide acts on KV3.1 channels by an open-channel blocker mechanism |
spellingShingle |
4-Chloro-3-nitro-N-butylbenzenesulfonamide acts on KV3.1 channels by an open-channel blocker mechanism Bassetto Junior, Carlos Alberto Zanutto [UNESP] KV3.1 N-alkylbenzenesulfonamides Open-channel blockers Patch-clamp |
title_short |
4-Chloro-3-nitro-N-butylbenzenesulfonamide acts on KV3.1 channels by an open-channel blocker mechanism |
title_full |
4-Chloro-3-nitro-N-butylbenzenesulfonamide acts on KV3.1 channels by an open-channel blocker mechanism |
title_fullStr |
4-Chloro-3-nitro-N-butylbenzenesulfonamide acts on KV3.1 channels by an open-channel blocker mechanism |
title_full_unstemmed |
4-Chloro-3-nitro-N-butylbenzenesulfonamide acts on KV3.1 channels by an open-channel blocker mechanism |
title_sort |
4-Chloro-3-nitro-N-butylbenzenesulfonamide acts on KV3.1 channels by an open-channel blocker mechanism |
author |
Bassetto Junior, Carlos Alberto Zanutto [UNESP] |
author_facet |
Bassetto Junior, Carlos Alberto Zanutto [UNESP] Varanda, Wamberto Antonio González, Eduardo René Pérez [UNESP] |
author_role |
author |
author2 |
Varanda, Wamberto Antonio González, Eduardo René Pérez [UNESP] |
author2_role |
author author |
dc.contributor.none.fl_str_mv |
Universidade Estadual Paulista (Unesp) Post-Graduate Program in Science and Material Technology Universidade de São Paulo (USP) |
dc.contributor.author.fl_str_mv |
Bassetto Junior, Carlos Alberto Zanutto [UNESP] Varanda, Wamberto Antonio González, Eduardo René Pérez [UNESP] |
dc.subject.por.fl_str_mv |
KV3.1 N-alkylbenzenesulfonamides Open-channel blockers Patch-clamp |
topic |
KV3.1 N-alkylbenzenesulfonamides Open-channel blockers Patch-clamp |
description |
The effects of 4-chloro-3-nitro-N-butylbenzenesulfonamide (SMD2) on KV3.1 channels, heterologous expressed in L-929 cells, were studied with the whole cell patch-clamp technique. SMD2 blocks KV3.1 in a reversible and use-dependent manner, with IC50 around 10 µM, and a Hill coefficient around 2. Although the conductance vs. voltage relationship in control condition can be described by a single Boltzmann function, two terms are necessary to describe the data in the presence of SMD2. The activation and deactivation time constants are weakly voltage dependent both for control and in the presence of SMD2. SMD2 does not change the channel selectivity and tail currents show a typical crossover phenomenon. The time course of inactivation has a fast and a slow component, and SMD2 significantly decreased their values. Steady-state inactivation is best described by a Boltzmann equation with V1/2 (the voltage where the probability to find the channels in the inactivated state is 50%) and K (slope factor) equals to −22.9 ± 1.5 mV and 5.3 ± 0.9 mV for control, and −30.3 ± 1.3 mV and 6 ± 0.8 mV for SMD2, respectively. The action of SMD2 is enhanced by high frequency stimulation, and by the time the channel stays open. Taken together, our results suggest that SMD2 blocks the open conformation of KV3.1. From a pharmacological and therapeutic point of view, N-alkylsulfonamides may constitute a new class of pharmacological modulators of KV3.1. |
publishDate |
2017 |
dc.date.none.fl_str_mv |
2017-11-01 2018-12-11T17:14:36Z 2018-12-11T17:14:36Z |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
dc.type.driver.fl_str_mv |
info:eu-repo/semantics/article |
format |
article |
status_str |
publishedVersion |
dc.identifier.uri.fl_str_mv |
http://dx.doi.org/10.1007/s00726-017-2488-0 Amino Acids, v. 49, n. 11, p. 1895-1906, 2017. 1438-2199 0939-4451 http://hdl.handle.net/11449/175152 10.1007/s00726-017-2488-0 2-s2.0-85029148997 2-s2.0-85029148997.pdf |
url |
http://dx.doi.org/10.1007/s00726-017-2488-0 http://hdl.handle.net/11449/175152 |
identifier_str_mv |
Amino Acids, v. 49, n. 11, p. 1895-1906, 2017. 1438-2199 0939-4451 10.1007/s00726-017-2488-0 2-s2.0-85029148997 2-s2.0-85029148997.pdf |
dc.language.iso.fl_str_mv |
eng |
language |
eng |
dc.relation.none.fl_str_mv |
Amino Acids 1,135 1,135 |
dc.rights.driver.fl_str_mv |
info:eu-repo/semantics/openAccess |
eu_rights_str_mv |
openAccess |
dc.format.none.fl_str_mv |
1895-1906 application/pdf |
dc.source.none.fl_str_mv |
Scopus reponame:Repositório Institucional da UNESP instname:Universidade Estadual Paulista (UNESP) instacron:UNESP |
instname_str |
Universidade Estadual Paulista (UNESP) |
instacron_str |
UNESP |
institution |
UNESP |
reponame_str |
Repositório Institucional da UNESP |
collection |
Repositório Institucional da UNESP |
repository.name.fl_str_mv |
Repositório Institucional da UNESP - Universidade Estadual Paulista (UNESP) |
repository.mail.fl_str_mv |
|
_version_ |
1808128841703489536 |