Functional and structural interaction of (-)-Reboxetine with the human α4β2 nicotinic acetylcholine receptor

Autores
Arias, Hugo Rubén; Fedorov, Nikolai B.; Benson, Lisa C.; Lippiello, Patrick M.; Gatto, Greg J.; Feuerbach, Dominik; Ortells, Marcelo Oscar
Año de publicación
2013
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
The interaction of the selective norepinephrine reuptake inhibitor (-)-reboxetine with the human α4β2 nicotinic acetylcholine receptor (nAChR) in different conformational states was studied by several functional and structural approaches. Patch-clamp and Ca(2+)-influx results indicate that (-)-reboxetine does not activate hα4β2 nAChRs via interaction with the orthosteric sites, but inhibits agonist-induced hα4β2 activation by a noncompetitive mechanism. Consistently, the results from the electrophysiology-based functional approach suggest that (-)-reboxetine may act via open channel block; therefore, it is capable of producing a use-dependent type of inhibition of the hα4β2 nAChR function. We tested whether (-)-reboxetine binds to the luminal [(3)H]imipramine site. The results indicate that, although (-)-reboxetine binds with low affinity to this site, it discriminates between the resting and desensitized hα4β2 nAChR ion channels. Patch-clamp results also indicate that (-)-reboxetine progressively inhibits the hα4β2 nAChR with two-fold higher potency at the end of one-second application of agonist, compared with the peak current. The molecular docking studies show that (-)-reboxetine blocks the ion channel at the level of the imipramine locus, between M2 rings 6´ and 14´. In addition, we found a (-)-reboxetine conformer that docks in the helix bundle of the α4 subunit, near the middle region. According to molecular dynamics simulations, (-)-reboxetine binding is stable for both sites, albeit less stable than imipramine. The interaction of these drugs with the helix bundle might alter allostericaly the functionality of the channel. In conclusion, the clinical action of (-)-reboxetine may be produced (at least partially) by its inhibitory action on hα4β2 nAChRs.
Fil: Arias, Hugo Rubén. California Northstate University. College of Medicine. Department of Medical Education; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Fedorov, Nikolai B.. Targacept, Inc.; Estados Unidos
Fil: Benson, Lisa C.. Targacept, Inc.; Estados Unidos
Fil: Lippiello, Patrick M.. Targacept, Inc.; Estados Unidos
Fil: Gatto, Greg J.. Targacept, Inc.; Estados Unidos
Fil: Feuerbach, Dominik. Novartis Institutes for Biomedical Research; Suiza. Universidad de Morón. Facultad de Medicina; Argentina
Fil: Ortells, Marcelo Oscar. Novartis Institutes for Biomedical Research; Suiza. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Morón; Argentina
Materia
Nicotinic Acetylcholine Receptors
Ion Channel
Reboxetine
Pharmacology
Antidepressant
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:11336/21142

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oai_identifier_str oai:ri.conicet.gov.ar:11336/21142
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Functional and structural interaction of (-)-Reboxetine with the human α4β2 nicotinic acetylcholine receptorArias, Hugo RubénFedorov, Nikolai B.Benson, Lisa C.Lippiello, Patrick M.Gatto, Greg J.Feuerbach, DominikOrtells, Marcelo OscarNicotinic Acetylcholine ReceptorsIon ChannelReboxetinePharmacologyAntidepressanthttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1https://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1The interaction of the selective norepinephrine reuptake inhibitor (-)-reboxetine with the human α4β2 nicotinic acetylcholine receptor (nAChR) in different conformational states was studied by several functional and structural approaches. Patch-clamp and Ca(2+)-influx results indicate that (-)-reboxetine does not activate hα4β2 nAChRs via interaction with the orthosteric sites, but inhibits agonist-induced hα4β2 activation by a noncompetitive mechanism. Consistently, the results from the electrophysiology-based functional approach suggest that (-)-reboxetine may act via open channel block; therefore, it is capable of producing a use-dependent type of inhibition of the hα4β2 nAChR function. We tested whether (-)-reboxetine binds to the luminal [(3)H]imipramine site. The results indicate that, although (-)-reboxetine binds with low affinity to this site, it discriminates between the resting and desensitized hα4β2 nAChR ion channels. Patch-clamp results also indicate that (-)-reboxetine progressively inhibits the hα4β2 nAChR with two-fold higher potency at the end of one-second application of agonist, compared with the peak current. The molecular docking studies show that (-)-reboxetine blocks the ion channel at the level of the imipramine locus, between M2 rings 6´ and 14´. In addition, we found a (-)-reboxetine conformer that docks in the helix bundle of the α4 subunit, near the middle region. According to molecular dynamics simulations, (-)-reboxetine binding is stable for both sites, albeit less stable than imipramine. The interaction of these drugs with the helix bundle might alter allostericaly the functionality of the channel. In conclusion, the clinical action of (-)-reboxetine may be produced (at least partially) by its inhibitory action on hα4β2 nAChRs.Fil: Arias, Hugo Rubén. California Northstate University. College of Medicine. Department of Medical Education; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Fedorov, Nikolai B.. Targacept, Inc.; Estados UnidosFil: Benson, Lisa C.. Targacept, Inc.; Estados UnidosFil: Lippiello, Patrick M.. Targacept, Inc.; Estados UnidosFil: Gatto, Greg J.. Targacept, Inc.; Estados UnidosFil: Feuerbach, Dominik. Novartis Institutes for Biomedical Research; Suiza. Universidad de Morón. Facultad de Medicina; ArgentinaFil: Ortells, Marcelo Oscar. Novartis Institutes for Biomedical Research; Suiza. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Morón; ArgentinaAmerican Society for Pharmacology and Experimental Therapeutics2013-01info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/21142Arias, Hugo Rubén; Fedorov, Nikolai B.; Benson, Lisa C.; Lippiello, Patrick M.; Gatto, Greg J.; et al.; Functional and structural interaction of (-)-Reboxetine with the human α4β2 nicotinic acetylcholine receptor; American Society for Pharmacology and Experimental Therapeutics; Journal of Pharmacology and Experimental Therapeutics; 344; 1; 1-2013; 113-1230022-3565CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/http://jpet.aspetjournals.org/content/344/1/113info:eu-repo/semantics/altIdentifier/doi/10.1124/jpet.112.197905info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-03T09:44:40Zoai:ri.conicet.gov.ar:11336/21142instacron: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:34982025-09-03 09:44:40.616CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Functional and structural interaction of (-)-Reboxetine with the human α4β2 nicotinic acetylcholine receptor
title Functional and structural interaction of (-)-Reboxetine with the human α4β2 nicotinic acetylcholine receptor
spellingShingle Functional and structural interaction of (-)-Reboxetine with the human α4β2 nicotinic acetylcholine receptor
Arias, Hugo Rubén
Nicotinic Acetylcholine Receptors
Ion Channel
Reboxetine
Pharmacology
Antidepressant
title_short Functional and structural interaction of (-)-Reboxetine with the human α4β2 nicotinic acetylcholine receptor
title_full Functional and structural interaction of (-)-Reboxetine with the human α4β2 nicotinic acetylcholine receptor
title_fullStr Functional and structural interaction of (-)-Reboxetine with the human α4β2 nicotinic acetylcholine receptor
title_full_unstemmed Functional and structural interaction of (-)-Reboxetine with the human α4β2 nicotinic acetylcholine receptor
title_sort Functional and structural interaction of (-)-Reboxetine with the human α4β2 nicotinic acetylcholine receptor
dc.creator.none.fl_str_mv Arias, Hugo Rubén
Fedorov, Nikolai B.
Benson, Lisa C.
Lippiello, Patrick M.
Gatto, Greg J.
Feuerbach, Dominik
Ortells, Marcelo Oscar
author Arias, Hugo Rubén
author_facet Arias, Hugo Rubén
Fedorov, Nikolai B.
Benson, Lisa C.
Lippiello, Patrick M.
Gatto, Greg J.
Feuerbach, Dominik
Ortells, Marcelo Oscar
author_role author
author2 Fedorov, Nikolai B.
Benson, Lisa C.
Lippiello, Patrick M.
Gatto, Greg J.
Feuerbach, Dominik
Ortells, Marcelo Oscar
author2_role author
author
author
author
author
author
dc.subject.none.fl_str_mv Nicotinic Acetylcholine Receptors
Ion Channel
Reboxetine
Pharmacology
Antidepressant
topic Nicotinic Acetylcholine Receptors
Ion Channel
Reboxetine
Pharmacology
Antidepressant
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 the selective norepinephrine reuptake inhibitor (-)-reboxetine with the human α4β2 nicotinic acetylcholine receptor (nAChR) in different conformational states was studied by several functional and structural approaches. Patch-clamp and Ca(2+)-influx results indicate that (-)-reboxetine does not activate hα4β2 nAChRs via interaction with the orthosteric sites, but inhibits agonist-induced hα4β2 activation by a noncompetitive mechanism. Consistently, the results from the electrophysiology-based functional approach suggest that (-)-reboxetine may act via open channel block; therefore, it is capable of producing a use-dependent type of inhibition of the hα4β2 nAChR function. We tested whether (-)-reboxetine binds to the luminal [(3)H]imipramine site. The results indicate that, although (-)-reboxetine binds with low affinity to this site, it discriminates between the resting and desensitized hα4β2 nAChR ion channels. Patch-clamp results also indicate that (-)-reboxetine progressively inhibits the hα4β2 nAChR with two-fold higher potency at the end of one-second application of agonist, compared with the peak current. The molecular docking studies show that (-)-reboxetine blocks the ion channel at the level of the imipramine locus, between M2 rings 6´ and 14´. In addition, we found a (-)-reboxetine conformer that docks in the helix bundle of the α4 subunit, near the middle region. According to molecular dynamics simulations, (-)-reboxetine binding is stable for both sites, albeit less stable than imipramine. The interaction of these drugs with the helix bundle might alter allostericaly the functionality of the channel. In conclusion, the clinical action of (-)-reboxetine may be produced (at least partially) by its inhibitory action on hα4β2 nAChRs.
Fil: Arias, Hugo Rubén. California Northstate University. College of Medicine. Department of Medical Education; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Fedorov, Nikolai B.. Targacept, Inc.; Estados Unidos
Fil: Benson, Lisa C.. Targacept, Inc.; Estados Unidos
Fil: Lippiello, Patrick M.. Targacept, Inc.; Estados Unidos
Fil: Gatto, Greg J.. Targacept, Inc.; Estados Unidos
Fil: Feuerbach, Dominik. Novartis Institutes for Biomedical Research; Suiza. Universidad de Morón. Facultad de Medicina; Argentina
Fil: Ortells, Marcelo Oscar. Novartis Institutes for Biomedical Research; Suiza. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Morón; Argentina
description The interaction of the selective norepinephrine reuptake inhibitor (-)-reboxetine with the human α4β2 nicotinic acetylcholine receptor (nAChR) in different conformational states was studied by several functional and structural approaches. Patch-clamp and Ca(2+)-influx results indicate that (-)-reboxetine does not activate hα4β2 nAChRs via interaction with the orthosteric sites, but inhibits agonist-induced hα4β2 activation by a noncompetitive mechanism. Consistently, the results from the electrophysiology-based functional approach suggest that (-)-reboxetine may act via open channel block; therefore, it is capable of producing a use-dependent type of inhibition of the hα4β2 nAChR function. We tested whether (-)-reboxetine binds to the luminal [(3)H]imipramine site. The results indicate that, although (-)-reboxetine binds with low affinity to this site, it discriminates between the resting and desensitized hα4β2 nAChR ion channels. Patch-clamp results also indicate that (-)-reboxetine progressively inhibits the hα4β2 nAChR with two-fold higher potency at the end of one-second application of agonist, compared with the peak current. The molecular docking studies show that (-)-reboxetine blocks the ion channel at the level of the imipramine locus, between M2 rings 6´ and 14´. In addition, we found a (-)-reboxetine conformer that docks in the helix bundle of the α4 subunit, near the middle region. According to molecular dynamics simulations, (-)-reboxetine binding is stable for both sites, albeit less stable than imipramine. The interaction of these drugs with the helix bundle might alter allostericaly the functionality of the channel. In conclusion, the clinical action of (-)-reboxetine may be produced (at least partially) by its inhibitory action on hα4β2 nAChRs.
publishDate 2013
dc.date.none.fl_str_mv 2013-01
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/11336/21142
Arias, Hugo Rubén; Fedorov, Nikolai B.; Benson, Lisa C.; Lippiello, Patrick M.; Gatto, Greg J.; et al.; Functional and structural interaction of (-)-Reboxetine with the human α4β2 nicotinic acetylcholine receptor; American Society for Pharmacology and Experimental Therapeutics; Journal of Pharmacology and Experimental Therapeutics; 344; 1; 1-2013; 113-123
0022-3565
CONICET Digital
CONICET
url http://hdl.handle.net/11336/21142
identifier_str_mv Arias, Hugo Rubén; Fedorov, Nikolai B.; Benson, Lisa C.; Lippiello, Patrick M.; Gatto, Greg J.; et al.; Functional and structural interaction of (-)-Reboxetine with the human α4β2 nicotinic acetylcholine receptor; American Society for Pharmacology and Experimental Therapeutics; Journal of Pharmacology and Experimental Therapeutics; 344; 1; 1-2013; 113-123
0022-3565
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/url/http://jpet.aspetjournals.org/content/344/1/113
info:eu-repo/semantics/altIdentifier/doi/10.1124/jpet.112.197905
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 American Society for Pharmacology and Experimental Therapeutics
publisher.none.fl_str_mv American Society for Pharmacology and Experimental Therapeutics
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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