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
- Institución
- Consejo Nacional de Investigaciones Científicas y Técnicas
- OAI Identificador
- oai:ri.conicet.gov.ar:11336/21142
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CONICET Digital (CONICET) |
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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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1842268682090184704 |
score |
13.13397 |