Molecular mechanisms of inhibition of nicotinic acetylcholine receptors by tricyclic antidepressants

Autores
Gumilar, Fernanda Andrea; Arias, Hugo Rubén; Spitzmaul, Guillermo Federico; Bouzat, Cecilia Beatriz
Año de publicación
2003
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
In addition to their well known actions on monoamine reuptake, tricyclic antidepressants have been shown to modulate ligand-gated ion channels (LGICs). Since the muscle nicotinic acetylcholine receptor (AChR) has been the model for studying structure-function relationships of LGICs, we analyzed the action of tricyclic antidepressants on this type of AChR at both single-channel and macroscopic current levels. We also determined their effects on ACh equilibrium binding and their interactions with the different conformational states of the AChR. Antidepressants produce a significant concentration-dependent decrease in the duration of clusters of single-channels (eight fold at 20 μM). They also decrease the peak amplitude and increase the decay rate of currents elicited by rapid perfusion of ACh to outside-out patches. In equilibrium binding assays, antidepressants promote the typical high-affinity desensitized state and inhibit binding of [piperidyl-3,4-3H (N)]-(N-(1-(2-thienyl) cyclohexyl)-3,4-piperidine ([3H]TCP) to its locus in resting and desensitized AChRs. The results indicate that tricyclic antidepressants: (i) interact with resting (closed), open, and desensitized channels; (ii) do not affect significantly channel opening and closing rates; (iii) do not act as fast open-channel blockers; (iv) inhibit activation of resting channels; and (v) may increase the rate of long-lived desensitization from the open state.
Fil: Gumilar, Fernanda Andrea. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Investigaciones Bioquímicas de Bahía Blanca. Universidad Nacional del Sur. Instituto de Investigaciones Bioquímicas de Bahía Blanca; Argentina
Fil: Arias, Hugo Rubén. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca; Argentina. Western University of Health Sciences, California; Estados Unidos
Fil: Spitzmaul, Guillermo Federico. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Investigaciones Bioquímicas de Bahía Blanca. Universidad Nacional del Sur. Instituto de Investigaciones Bioquímicas de Bahía Blanca; Argentina
Fil: Bouzat, Cecilia Beatriz. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Investigaciones Bioquímicas de Bahía Blanca. Universidad Nacional del Sur. Instituto de Investigaciones Bioquímicas de Bahía Blanca; Argentina
Materia
Acetylcholine
Nicotinic Receptor
Noncompetitive Inhibitor
Tricyclic 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:11336/53354
Acceder
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oai_identifier_str oai:ri.conicet.gov.ar:11336/53354
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Molecular mechanisms of inhibition of nicotinic acetylcholine receptors by tricyclic antidepressantsGumilar, Fernanda AndreaArias, Hugo RubénSpitzmaul, Guillermo FedericoBouzat, Cecilia BeatrizAcetylcholineNicotinic ReceptorNoncompetitive InhibitorTricyclic Antidepressanthttps://purl.org/becyt/ford/3.1https://purl.org/becyt/ford/3In addition to their well known actions on monoamine reuptake, tricyclic antidepressants have been shown to modulate ligand-gated ion channels (LGICs). Since the muscle nicotinic acetylcholine receptor (AChR) has been the model for studying structure-function relationships of LGICs, we analyzed the action of tricyclic antidepressants on this type of AChR at both single-channel and macroscopic current levels. We also determined their effects on ACh equilibrium binding and their interactions with the different conformational states of the AChR. Antidepressants produce a significant concentration-dependent decrease in the duration of clusters of single-channels (eight fold at 20 μM). They also decrease the peak amplitude and increase the decay rate of currents elicited by rapid perfusion of ACh to outside-out patches. In equilibrium binding assays, antidepressants promote the typical high-affinity desensitized state and inhibit binding of [piperidyl-3,4-3H (N)]-(N-(1-(2-thienyl) cyclohexyl)-3,4-piperidine ([3H]TCP) to its locus in resting and desensitized AChRs. The results indicate that tricyclic antidepressants: (i) interact with resting (closed), open, and desensitized channels; (ii) do not affect significantly channel opening and closing rates; (iii) do not act as fast open-channel blockers; (iv) inhibit activation of resting channels; and (v) may increase the rate of long-lived desensitization from the open state.Fil: Gumilar, Fernanda Andrea. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Investigaciones Bioquímicas de Bahía Blanca. Universidad Nacional del Sur. Instituto de Investigaciones Bioquímicas de Bahía Blanca; ArgentinaFil: Arias, Hugo Rubén. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca; Argentina. Western University of Health Sciences, California; Estados UnidosFil: Spitzmaul, Guillermo Federico. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Investigaciones Bioquímicas de Bahía Blanca. Universidad Nacional del Sur. Instituto de Investigaciones Bioquímicas de Bahía Blanca; ArgentinaFil: Bouzat, Cecilia Beatriz. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Investigaciones Bioquímicas de Bahía Blanca. Universidad Nacional del Sur. Instituto de Investigaciones Bioquímicas de Bahía Blanca; ArgentinaPergamon-Elsevier Science Ltd2003-12info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfapplication/pdfapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/53354Gumilar, Fernanda Andrea; Arias, Hugo Rubén; Spitzmaul, Guillermo Federico; Bouzat, Cecilia Beatriz; Molecular mechanisms of inhibition of nicotinic acetylcholine receptors by tricyclic antidepressants; Pergamon-Elsevier Science Ltd; Neuropharmacology; 45; 7; 12-2003; 964-9760028-3908CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://www.sciencedirect.com/science/article/pii/S0028390803002478info:eu-repo/semantics/altIdentifier/doi/10.1016/S0028-3908(03)00247-8info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-03T10:05:56Zoai:ri.conicet.gov.ar:11336/53354instacron: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 10:05:57.046CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Molecular mechanisms of inhibition of nicotinic acetylcholine receptors by tricyclic antidepressants
title Molecular mechanisms of inhibition of nicotinic acetylcholine receptors by tricyclic antidepressants
spellingShingle Molecular mechanisms of inhibition of nicotinic acetylcholine receptors by tricyclic antidepressants
Gumilar, Fernanda Andrea
Acetylcholine
Nicotinic Receptor
Noncompetitive Inhibitor
Tricyclic Antidepressant
title_short Molecular mechanisms of inhibition of nicotinic acetylcholine receptors by tricyclic antidepressants
title_full Molecular mechanisms of inhibition of nicotinic acetylcholine receptors by tricyclic antidepressants
title_fullStr Molecular mechanisms of inhibition of nicotinic acetylcholine receptors by tricyclic antidepressants
title_full_unstemmed Molecular mechanisms of inhibition of nicotinic acetylcholine receptors by tricyclic antidepressants
title_sort Molecular mechanisms of inhibition of nicotinic acetylcholine receptors by tricyclic antidepressants
dc.creator.none.fl_str_mv Gumilar, Fernanda Andrea
Arias, Hugo Rubén
Spitzmaul, Guillermo Federico
Bouzat, Cecilia Beatriz
author Gumilar, Fernanda Andrea
author_facet Gumilar, Fernanda Andrea
Arias, Hugo Rubén
Spitzmaul, Guillermo Federico
Bouzat, Cecilia Beatriz
author_role author
author2 Arias, Hugo Rubén
Spitzmaul, Guillermo Federico
Bouzat, Cecilia Beatriz
author2_role author
author
author
dc.subject.none.fl_str_mv Acetylcholine
Nicotinic Receptor
Noncompetitive Inhibitor
Tricyclic Antidepressant
topic Acetylcholine
Nicotinic Receptor
Noncompetitive Inhibitor
Tricyclic Antidepressant
purl_subject.fl_str_mv https://purl.org/becyt/ford/3.1
https://purl.org/becyt/ford/3
dc.description.none.fl_txt_mv In addition to their well known actions on monoamine reuptake, tricyclic antidepressants have been shown to modulate ligand-gated ion channels (LGICs). Since the muscle nicotinic acetylcholine receptor (AChR) has been the model for studying structure-function relationships of LGICs, we analyzed the action of tricyclic antidepressants on this type of AChR at both single-channel and macroscopic current levels. We also determined their effects on ACh equilibrium binding and their interactions with the different conformational states of the AChR. Antidepressants produce a significant concentration-dependent decrease in the duration of clusters of single-channels (eight fold at 20 μM). They also decrease the peak amplitude and increase the decay rate of currents elicited by rapid perfusion of ACh to outside-out patches. In equilibrium binding assays, antidepressants promote the typical high-affinity desensitized state and inhibit binding of [piperidyl-3,4-3H (N)]-(N-(1-(2-thienyl) cyclohexyl)-3,4-piperidine ([3H]TCP) to its locus in resting and desensitized AChRs. The results indicate that tricyclic antidepressants: (i) interact with resting (closed), open, and desensitized channels; (ii) do not affect significantly channel opening and closing rates; (iii) do not act as fast open-channel blockers; (iv) inhibit activation of resting channels; and (v) may increase the rate of long-lived desensitization from the open state.
Fil: Gumilar, Fernanda Andrea. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Investigaciones Bioquímicas de Bahía Blanca. Universidad Nacional del Sur. Instituto de Investigaciones Bioquímicas de Bahía Blanca; Argentina
Fil: Arias, Hugo Rubén. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca; Argentina. Western University of Health Sciences, California; Estados Unidos
Fil: Spitzmaul, Guillermo Federico. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Investigaciones Bioquímicas de Bahía Blanca. Universidad Nacional del Sur. Instituto de Investigaciones Bioquímicas de Bahía Blanca; Argentina
Fil: Bouzat, Cecilia Beatriz. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Investigaciones Bioquímicas de Bahía Blanca. Universidad Nacional del Sur. Instituto de Investigaciones Bioquímicas de Bahía Blanca; Argentina
description In addition to their well known actions on monoamine reuptake, tricyclic antidepressants have been shown to modulate ligand-gated ion channels (LGICs). Since the muscle nicotinic acetylcholine receptor (AChR) has been the model for studying structure-function relationships of LGICs, we analyzed the action of tricyclic antidepressants on this type of AChR at both single-channel and macroscopic current levels. We also determined their effects on ACh equilibrium binding and their interactions with the different conformational states of the AChR. Antidepressants produce a significant concentration-dependent decrease in the duration of clusters of single-channels (eight fold at 20 μM). They also decrease the peak amplitude and increase the decay rate of currents elicited by rapid perfusion of ACh to outside-out patches. In equilibrium binding assays, antidepressants promote the typical high-affinity desensitized state and inhibit binding of [piperidyl-3,4-3H (N)]-(N-(1-(2-thienyl) cyclohexyl)-3,4-piperidine ([3H]TCP) to its locus in resting and desensitized AChRs. The results indicate that tricyclic antidepressants: (i) interact with resting (closed), open, and desensitized channels; (ii) do not affect significantly channel opening and closing rates; (iii) do not act as fast open-channel blockers; (iv) inhibit activation of resting channels; and (v) may increase the rate of long-lived desensitization from the open state.
publishDate 2003
dc.date.none.fl_str_mv 2003-12
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/11336/53354
Gumilar, Fernanda Andrea; Arias, Hugo Rubén; Spitzmaul, Guillermo Federico; Bouzat, Cecilia Beatriz; Molecular mechanisms of inhibition of nicotinic acetylcholine receptors by tricyclic antidepressants; Pergamon-Elsevier Science Ltd; Neuropharmacology; 45; 7; 12-2003; 964-976
0028-3908
CONICET Digital
CONICET
url http://hdl.handle.net/11336/53354
identifier_str_mv Gumilar, Fernanda Andrea; Arias, Hugo Rubén; Spitzmaul, Guillermo Federico; Bouzat, Cecilia Beatriz; Molecular mechanisms of inhibition of nicotinic acetylcholine receptors by tricyclic antidepressants; Pergamon-Elsevier Science Ltd; Neuropharmacology; 45; 7; 12-2003; 964-976
0028-3908
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/url/https://www.sciencedirect.com/science/article/pii/S0028390803002478
info:eu-repo/semantics/altIdentifier/doi/10.1016/S0028-3908(03)00247-8
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
application/pdf
application/pdf
application/pdf
application/pdf
dc.publisher.none.fl_str_mv Pergamon-Elsevier Science Ltd
publisher.none.fl_str_mv Pergamon-Elsevier Science Ltd
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 13.13397

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