(−)-Reboxetine inhibits muscle nicotinic acetylcholine receptors by interacting with luminal and non-luminal sites

Autores
Arias, Hugo Rubén; Ortells, Marcelo Oscar; Feuerbach, Dominik
Año de publicación
2013
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
The interaction of (−)-reboxetine, a non-tricyclic norepinephrine selective reuptake inhibitor, with muscle-type nicotinic acetylcholine receptors (AChRs) in different conformational states was studied by functional and structural approaches. The results established that (−)-reboxetine: (a) inhibits (±)-epibatidine-induced Ca2+ influx in human (h) muscle embryonic (hα1β1γδ) and adult (hα1β1εδ) AChRs in a non-competitive manner and with potencies IC50 = 3.86 ± 0.49 and 1.92 ± 0.48 μM, respectively, (b) binds to the [3H]TCP site with ∼13-fold higher affinity when the Torpedo AChR is in the desensitized state compared to the resting state, (c) enhances [3H]cytisine binding to the resting but activatableTorpedo AChR but not to the desensitized AChR, suggesting desensitizing properties, (d) overlaps the PCP luminal site located between rings 6′ and 13′ in the Torpedo but not human muscle AChRs. In silico mutation results indicate that ring 9′ is the minimum structural component for (−)-reboxetine binding, and (e) interacts to non-luminal sites located within the transmembrane segments from the Torpedo AChR γ subunit, and at the α1/ε transmembrane interface from the adult muscle AChR. In conclusion, (−)-reboxetine non-competitively inhibits muscle AChRs by binding to the TCP luminal site and by inducing receptor desensitization (maybe by interacting with non-luminal sites), a mechanism that is shared by tricyclic antidepressants.
Fil: Arias, Hugo Rubén. California Northstate University College of Medicine; Estados Unidos
Fil: Ortells, Marcelo Oscar. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Morón. Facultad de Medicina; Argentina
Fil: Feuerbach, Dominik. Novartis Institutes for Biomedical Research; Suiza
Materia
Reboxetine
Nicotinic Acetylcholine Receptors
Ion Channel
Antidepressant
Conformational States
Norepinephrine Selective Reuptake Inhibitor
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/26542
Acceder
id CONICETDig_16a745d090522fabe2cd2f32b59e049e
oai_identifier_str oai:ri.conicet.gov.ar:11336/26542
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling (−)-Reboxetine inhibits muscle nicotinic acetylcholine receptors by interacting with luminal and non-luminal sitesArias, Hugo RubénOrtells, Marcelo OscarFeuerbach, DominikReboxetineNicotinic Acetylcholine ReceptorsIon ChannelAntidepressantConformational StatesNorepinephrine Selective Reuptake Inhibitorhttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1https://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1The interaction of (−)-reboxetine, a non-tricyclic norepinephrine selective reuptake inhibitor, with muscle-type nicotinic acetylcholine receptors (AChRs) in different conformational states was studied by functional and structural approaches. The results established that (−)-reboxetine: (a) inhibits (±)-epibatidine-induced Ca2+ influx in human (h) muscle embryonic (hα1β1γδ) and adult (hα1β1εδ) AChRs in a non-competitive manner and with potencies IC50 = 3.86 ± 0.49 and 1.92 ± 0.48 μM, respectively, (b) binds to the [3H]TCP site with ∼13-fold higher affinity when the Torpedo AChR is in the desensitized state compared to the resting state, (c) enhances [3H]cytisine binding to the resting but activatableTorpedo AChR but not to the desensitized AChR, suggesting desensitizing properties, (d) overlaps the PCP luminal site located between rings 6′ and 13′ in the Torpedo but not human muscle AChRs. In silico mutation results indicate that ring 9′ is the minimum structural component for (−)-reboxetine binding, and (e) interacts to non-luminal sites located within the transmembrane segments from the Torpedo AChR γ subunit, and at the α1/ε transmembrane interface from the adult muscle AChR. In conclusion, (−)-reboxetine non-competitively inhibits muscle AChRs by binding to the TCP luminal site and by inducing receptor desensitization (maybe by interacting with non-luminal sites), a mechanism that is shared by tricyclic antidepressants.Fil: Arias, Hugo Rubén. California Northstate University College of Medicine; Estados UnidosFil: Ortells, Marcelo Oscar. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Morón. Facultad de Medicina; ArgentinaFil: Feuerbach, Dominik. Novartis Institutes for Biomedical Research; SuizaElsevier2013-07info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/26542Arias, Hugo Rubén; Ortells, Marcelo Oscar; Feuerbach, Dominik; (−)-Reboxetine inhibits muscle nicotinic acetylcholine receptors by interacting with luminal and non-luminal sites; Elsevier; Neurochemistry International; 63; 5; 7-2013; 423-4310197-0186CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/doi/10.1016/j.neuint.2013.07.009info:eu-repo/semantics/altIdentifier/url/http://www.sciencedirect.com/science/article/pii/S0197018613002040info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-29T10:40:57Zoai:ri.conicet.gov.ar:11336/26542instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-09-29 10:40:57.823CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv (−)-Reboxetine inhibits muscle nicotinic acetylcholine receptors by interacting with luminal and non-luminal sites
title (−)-Reboxetine inhibits muscle nicotinic acetylcholine receptors by interacting with luminal and non-luminal sites
spellingShingle (−)-Reboxetine inhibits muscle nicotinic acetylcholine receptors by interacting with luminal and non-luminal sites
Arias, Hugo Rubén
Reboxetine
Nicotinic Acetylcholine Receptors
Ion Channel
Antidepressant
Conformational States
Norepinephrine Selective Reuptake Inhibitor
title_short (−)-Reboxetine inhibits muscle nicotinic acetylcholine receptors by interacting with luminal and non-luminal sites
title_full (−)-Reboxetine inhibits muscle nicotinic acetylcholine receptors by interacting with luminal and non-luminal sites
title_fullStr (−)-Reboxetine inhibits muscle nicotinic acetylcholine receptors by interacting with luminal and non-luminal sites
title_full_unstemmed (−)-Reboxetine inhibits muscle nicotinic acetylcholine receptors by interacting with luminal and non-luminal sites
title_sort (−)-Reboxetine inhibits muscle nicotinic acetylcholine receptors by interacting with luminal and non-luminal sites
dc.creator.none.fl_str_mv Arias, Hugo Rubén
Ortells, Marcelo Oscar
Feuerbach, Dominik
author Arias, Hugo Rubén
author_facet Arias, Hugo Rubén
Ortells, Marcelo Oscar
Feuerbach, Dominik
author_role author
author2 Ortells, Marcelo Oscar
Feuerbach, Dominik
author2_role author
author
dc.subject.none.fl_str_mv Reboxetine
Nicotinic Acetylcholine Receptors
Ion Channel
Antidepressant
Conformational States
Norepinephrine Selective Reuptake Inhibitor
topic Reboxetine
Nicotinic Acetylcholine Receptors
Ion Channel
Antidepressant
Conformational States
Norepinephrine Selective Reuptake Inhibitor
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.6
https://purl.org/becyt/ford/1
https://purl.org/becyt/ford/1.6
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv The interaction of (−)-reboxetine, a non-tricyclic norepinephrine selective reuptake inhibitor, with muscle-type nicotinic acetylcholine receptors (AChRs) in different conformational states was studied by functional and structural approaches. The results established that (−)-reboxetine: (a) inhibits (±)-epibatidine-induced Ca2+ influx in human (h) muscle embryonic (hα1β1γδ) and adult (hα1β1εδ) AChRs in a non-competitive manner and with potencies IC50 = 3.86 ± 0.49 and 1.92 ± 0.48 μM, respectively, (b) binds to the [3H]TCP site with ∼13-fold higher affinity when the Torpedo AChR is in the desensitized state compared to the resting state, (c) enhances [3H]cytisine binding to the resting but activatableTorpedo AChR but not to the desensitized AChR, suggesting desensitizing properties, (d) overlaps the PCP luminal site located between rings 6′ and 13′ in the Torpedo but not human muscle AChRs. In silico mutation results indicate that ring 9′ is the minimum structural component for (−)-reboxetine binding, and (e) interacts to non-luminal sites located within the transmembrane segments from the Torpedo AChR γ subunit, and at the α1/ε transmembrane interface from the adult muscle AChR. In conclusion, (−)-reboxetine non-competitively inhibits muscle AChRs by binding to the TCP luminal site and by inducing receptor desensitization (maybe by interacting with non-luminal sites), a mechanism that is shared by tricyclic antidepressants.
Fil: Arias, Hugo Rubén. California Northstate University College of Medicine; Estados Unidos
Fil: Ortells, Marcelo Oscar. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Morón. Facultad de Medicina; Argentina
Fil: Feuerbach, Dominik. Novartis Institutes for Biomedical Research; Suiza
description The interaction of (−)-reboxetine, a non-tricyclic norepinephrine selective reuptake inhibitor, with muscle-type nicotinic acetylcholine receptors (AChRs) in different conformational states was studied by functional and structural approaches. The results established that (−)-reboxetine: (a) inhibits (±)-epibatidine-induced Ca2+ influx in human (h) muscle embryonic (hα1β1γδ) and adult (hα1β1εδ) AChRs in a non-competitive manner and with potencies IC50 = 3.86 ± 0.49 and 1.92 ± 0.48 μM, respectively, (b) binds to the [3H]TCP site with ∼13-fold higher affinity when the Torpedo AChR is in the desensitized state compared to the resting state, (c) enhances [3H]cytisine binding to the resting but activatableTorpedo AChR but not to the desensitized AChR, suggesting desensitizing properties, (d) overlaps the PCP luminal site located between rings 6′ and 13′ in the Torpedo but not human muscle AChRs. In silico mutation results indicate that ring 9′ is the minimum structural component for (−)-reboxetine binding, and (e) interacts to non-luminal sites located within the transmembrane segments from the Torpedo AChR γ subunit, and at the α1/ε transmembrane interface from the adult muscle AChR. In conclusion, (−)-reboxetine non-competitively inhibits muscle AChRs by binding to the TCP luminal site and by inducing receptor desensitization (maybe by interacting with non-luminal sites), a mechanism that is shared by tricyclic antidepressants.
publishDate 2013
dc.date.none.fl_str_mv 2013-07
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/26542
Arias, Hugo Rubén; Ortells, Marcelo Oscar; Feuerbach, Dominik; (−)-Reboxetine inhibits muscle nicotinic acetylcholine receptors by interacting with luminal and non-luminal sites; Elsevier; Neurochemistry International; 63; 5; 7-2013; 423-431
0197-0186
CONICET Digital
CONICET
url http://hdl.handle.net/11336/26542
identifier_str_mv Arias, Hugo Rubén; Ortells, Marcelo Oscar; Feuerbach, Dominik; (−)-Reboxetine inhibits muscle nicotinic acetylcholine receptors by interacting with luminal and non-luminal sites; Elsevier; Neurochemistry International; 63; 5; 7-2013; 423-431
0197-0186
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/doi/10.1016/j.neuint.2013.07.009
info:eu-repo/semantics/altIdentifier/url/http://www.sciencedirect.com/science/article/pii/S0197018613002040
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv Elsevier
publisher.none.fl_str_mv Elsevier
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str CONICET Digital (CONICET)
collection CONICET Digital (CONICET)
instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
repository.name.fl_str_mv CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas
repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
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score 13.070432

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