Tricyclic antidepressants inhibit homomeric Cys-loop receptors by acting at different conformational states

Autores
Gumilar, Fernanda Andrea; Bouzat, Cecilia Beatriz
Año de publicación
2008
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Tricyclic antidepressants not only inhibit monoamine reuptake but also modulate Cys-loop receptors. However, it is not understood how this modulation is involved in their therapeutic effects. We analyzed the mechanisms of inhibition of homomeric 5-HT(3A) and alpha7-5HT(3A) receptors by tricyclic antidepressants at the single-channel and macroscopic current levels. These drugs reduce agonist-evoked currents in a noncompetitive and concentration-dependent manner. When they act on the open state, the reduction is similar for both receptors and it is voltage-dependent, thus suggesting an open-channel block process in which the blocked channel can either close or remain stabilized. By acting on the resting state, tricyclic antidepressants reduce the peak current in a voltage-independent manner, with a potency 6-fold higher for 5-HT(3A) than for alpha7-5HT(3A) (IC(50): 6 microM and 1 microM for alpha7-5HT(3A) and 5-HT(3A), respectively). Thus, tricyclic antidepressants may act on closed channels at the unshared extracellular domain from where they inhibit channel opening. Single alpha7-5HT(3A) channels in the continued presence of tricyclic antidepressants show: i) reduced open durations, compatible with open-channel block; ii) reduced burst durations, compatible with closing of blocked channels; and iii) reduced frequency of opening events, compatible with both impaired opening and stabilization of a closed state. In summary, our study reveals that tricyclic antidepressants inhibit homomeric Cys-loop receptors by acting through different mechanisms at open and closed conformational states and probably at two different domains, namely, the pore in the open state and the extracellular domain in the closed 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: 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
Nicotinic Receptor
Cys-Loop Receptors
Tricyclic Antidepressants
Noncompetitive Inhibitors
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:11336/44466
Acceder
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network_acronym_str CONICETDig
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network_name_str CONICET Digital (CONICET)
spelling Tricyclic antidepressants inhibit homomeric Cys-loop receptors by acting at different conformational statesGumilar, Fernanda AndreaBouzat, Cecilia BeatrizNicotinic ReceptorCys-Loop ReceptorsTricyclic AntidepressantsNoncompetitive Inhibitorshttps://purl.org/becyt/ford/3.1https://purl.org/becyt/ford/3Tricyclic antidepressants not only inhibit monoamine reuptake but also modulate Cys-loop receptors. However, it is not understood how this modulation is involved in their therapeutic effects. We analyzed the mechanisms of inhibition of homomeric 5-HT(3A) and alpha7-5HT(3A) receptors by tricyclic antidepressants at the single-channel and macroscopic current levels. These drugs reduce agonist-evoked currents in a noncompetitive and concentration-dependent manner. When they act on the open state, the reduction is similar for both receptors and it is voltage-dependent, thus suggesting an open-channel block process in which the blocked channel can either close or remain stabilized. By acting on the resting state, tricyclic antidepressants reduce the peak current in a voltage-independent manner, with a potency 6-fold higher for 5-HT(3A) than for alpha7-5HT(3A) (IC(50): 6 microM and 1 microM for alpha7-5HT(3A) and 5-HT(3A), respectively). Thus, tricyclic antidepressants may act on closed channels at the unshared extracellular domain from where they inhibit channel opening. Single alpha7-5HT(3A) channels in the continued presence of tricyclic antidepressants show: i) reduced open durations, compatible with open-channel block; ii) reduced burst durations, compatible with closing of blocked channels; and iii) reduced frequency of opening events, compatible with both impaired opening and stabilization of a closed state. In summary, our study reveals that tricyclic antidepressants inhibit homomeric Cys-loop receptors by acting through different mechanisms at open and closed conformational states and probably at two different domains, namely, the pore in the open state and the extracellular domain in the closed 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: 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; ArgentinaElsevier Science2008-04info: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/11336/44466Gumilar, Fernanda Andrea; Bouzat, Cecilia Beatriz; Tricyclic antidepressants inhibit homomeric Cys-loop receptors by acting at different conformational states; Elsevier Science; European Journal of Pharmacology; 584; 1; 4-2008; 30-390014-2999CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://www.sciencedirect.com/science/article/pii/S0014299908000927info:eu-repo/semantics/altIdentifier/doi/10.1016/j.ejphar.2008.01.023info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-29T10:19:44Zoai:ri.conicet.gov.ar:11336/44466instacron: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 10:19:45.032CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Tricyclic antidepressants inhibit homomeric Cys-loop receptors by acting at different conformational states
title Tricyclic antidepressants inhibit homomeric Cys-loop receptors by acting at different conformational states
spellingShingle Tricyclic antidepressants inhibit homomeric Cys-loop receptors by acting at different conformational states
Gumilar, Fernanda Andrea
Nicotinic Receptor
Cys-Loop Receptors
Tricyclic Antidepressants
Noncompetitive Inhibitors
title_short Tricyclic antidepressants inhibit homomeric Cys-loop receptors by acting at different conformational states
title_full Tricyclic antidepressants inhibit homomeric Cys-loop receptors by acting at different conformational states
title_fullStr Tricyclic antidepressants inhibit homomeric Cys-loop receptors by acting at different conformational states
title_full_unstemmed Tricyclic antidepressants inhibit homomeric Cys-loop receptors by acting at different conformational states
title_sort Tricyclic antidepressants inhibit homomeric Cys-loop receptors by acting at different conformational states
dc.creator.none.fl_str_mv Gumilar, Fernanda Andrea
Bouzat, Cecilia Beatriz
author Gumilar, Fernanda Andrea
author_facet Gumilar, Fernanda Andrea
Bouzat, Cecilia Beatriz
author_role author
author2 Bouzat, Cecilia Beatriz
author2_role author
dc.subject.none.fl_str_mv Nicotinic Receptor
Cys-Loop Receptors
Tricyclic Antidepressants
Noncompetitive Inhibitors
topic Nicotinic Receptor
Cys-Loop Receptors
Tricyclic Antidepressants
Noncompetitive Inhibitors
purl_subject.fl_str_mv https://purl.org/becyt/ford/3.1
https://purl.org/becyt/ford/3
dc.description.none.fl_txt_mv Tricyclic antidepressants not only inhibit monoamine reuptake but also modulate Cys-loop receptors. However, it is not understood how this modulation is involved in their therapeutic effects. We analyzed the mechanisms of inhibition of homomeric 5-HT(3A) and alpha7-5HT(3A) receptors by tricyclic antidepressants at the single-channel and macroscopic current levels. These drugs reduce agonist-evoked currents in a noncompetitive and concentration-dependent manner. When they act on the open state, the reduction is similar for both receptors and it is voltage-dependent, thus suggesting an open-channel block process in which the blocked channel can either close or remain stabilized. By acting on the resting state, tricyclic antidepressants reduce the peak current in a voltage-independent manner, with a potency 6-fold higher for 5-HT(3A) than for alpha7-5HT(3A) (IC(50): 6 microM and 1 microM for alpha7-5HT(3A) and 5-HT(3A), respectively). Thus, tricyclic antidepressants may act on closed channels at the unshared extracellular domain from where they inhibit channel opening. Single alpha7-5HT(3A) channels in the continued presence of tricyclic antidepressants show: i) reduced open durations, compatible with open-channel block; ii) reduced burst durations, compatible with closing of blocked channels; and iii) reduced frequency of opening events, compatible with both impaired opening and stabilization of a closed state. In summary, our study reveals that tricyclic antidepressants inhibit homomeric Cys-loop receptors by acting through different mechanisms at open and closed conformational states and probably at two different domains, namely, the pore in the open state and the extracellular domain in the closed 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: 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 Tricyclic antidepressants not only inhibit monoamine reuptake but also modulate Cys-loop receptors. However, it is not understood how this modulation is involved in their therapeutic effects. We analyzed the mechanisms of inhibition of homomeric 5-HT(3A) and alpha7-5HT(3A) receptors by tricyclic antidepressants at the single-channel and macroscopic current levels. These drugs reduce agonist-evoked currents in a noncompetitive and concentration-dependent manner. When they act on the open state, the reduction is similar for both receptors and it is voltage-dependent, thus suggesting an open-channel block process in which the blocked channel can either close or remain stabilized. By acting on the resting state, tricyclic antidepressants reduce the peak current in a voltage-independent manner, with a potency 6-fold higher for 5-HT(3A) than for alpha7-5HT(3A) (IC(50): 6 microM and 1 microM for alpha7-5HT(3A) and 5-HT(3A), respectively). Thus, tricyclic antidepressants may act on closed channels at the unshared extracellular domain from where they inhibit channel opening. Single alpha7-5HT(3A) channels in the continued presence of tricyclic antidepressants show: i) reduced open durations, compatible with open-channel block; ii) reduced burst durations, compatible with closing of blocked channels; and iii) reduced frequency of opening events, compatible with both impaired opening and stabilization of a closed state. In summary, our study reveals that tricyclic antidepressants inhibit homomeric Cys-loop receptors by acting through different mechanisms at open and closed conformational states and probably at two different domains, namely, the pore in the open state and the extracellular domain in the closed state.
publishDate 2008
dc.date.none.fl_str_mv 2008-04
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/11336/44466
Gumilar, Fernanda Andrea; Bouzat, Cecilia Beatriz; Tricyclic antidepressants inhibit homomeric Cys-loop receptors by acting at different conformational states; Elsevier Science; European Journal of Pharmacology; 584; 1; 4-2008; 30-39
0014-2999
CONICET Digital
CONICET
url http://hdl.handle.net/11336/44466
identifier_str_mv Gumilar, Fernanda Andrea; Bouzat, Cecilia Beatriz; Tricyclic antidepressants inhibit homomeric Cys-loop receptors by acting at different conformational states; Elsevier Science; European Journal of Pharmacology; 584; 1; 4-2008; 30-39
0014-2999
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/S0014299908000927
info:eu-repo/semantics/altIdentifier/doi/10.1016/j.ejphar.2008.01.023
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 Elsevier Science
publisher.none.fl_str_mv Elsevier Science
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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