Mechanism of 5-HT3 receptor activation and modulation by allosteric drugs

Autores
Rodriguez Araujo, Noelia; Fabiani, Camila; Bouzat, Cecilia Beatriz; Corradi, Jeremias
Año de publicación
2018
Idioma
inglés
Tipo de recurso
documento de conferencia
Estado
versión publicada
Descripción
Serotonin type 3 receptors (5-HT3) are cation-selective channels that belong to the Cys-loop receptor family. They are involved in fast excitatory transmission in central and peripheral nervous systems and are implicated in gastrointestinal and neurological functions. Five different subunits (A-E) have been identified in humans, and the A subunit is the only one capable of forming functional homomeric receptors (5-HT3A). These receptors are activated by agonist binding to orthosteric sites located at the interfaces between two adjacent subunits at the extracellular region. Carvacrol and thymol have been classified as positive allosteric modulators that also act as allosteric agonists (ago-PAMs). To characterize their mechanism of activation and modulation we used the high- conductance form of the 5-HT3A receptor that allows detection of single-channel openings from patch-clamp recordings. We observed that both ligands activate the receptor, eliciting openings in quick succession grouped in clusters of high open probability. Mean closed, open and cluster durations remained constant at all agonist concentrations tested. When each ago-PAM was evaluated in the presence of tryptamine (an orthosteric agonist), we observed events with mean open durations similar to those observed in the presence of tryptamine alone, but cluster duration was clearly prolonged probably due to decreased desensitization. These results suggest that the mechanism of activation is governed by the orthosteric agonist while the allosteric drug is only acting as a potentiator. Altogether, our results describe the mechanism underlying human 5-HT3A receptor activation and modulation by two allosteric agonists and provide relevant information for the design of more efficacious and specific drugs.
Fil: Rodriguez Araujo, Noelia. 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: Fabiani, Camila. 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
Fil: Corradi, Jeremias. 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
XLVII Reunión Anual de la Sociedad Argentina de Biofísica (SAB)
La Plata
Argentina
Sociedad Argentina de Biofísica
Materia
SEROTONIN
HETEROMERIC RECEPTORS
PATCH-CLAMP
MODULATION
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:11336/231789
Acceder
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oai_identifier_str oai:ri.conicet.gov.ar:11336/231789
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Mechanism of 5-HT3 receptor activation and modulation by allosteric drugsRodriguez Araujo, NoeliaFabiani, CamilaBouzat, Cecilia BeatrizCorradi, JeremiasSEROTONINHETEROMERIC RECEPTORSPATCH-CLAMPMODULATIONhttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1Serotonin type 3 receptors (5-HT3) are cation-selective channels that belong to the Cys-loop receptor family. They are involved in fast excitatory transmission in central and peripheral nervous systems and are implicated in gastrointestinal and neurological functions. Five different subunits (A-E) have been identified in humans, and the A subunit is the only one capable of forming functional homomeric receptors (5-HT3A). These receptors are activated by agonist binding to orthosteric sites located at the interfaces between two adjacent subunits at the extracellular region. Carvacrol and thymol have been classified as positive allosteric modulators that also act as allosteric agonists (ago-PAMs). To characterize their mechanism of activation and modulation we used the high- conductance form of the 5-HT3A receptor that allows detection of single-channel openings from patch-clamp recordings. We observed that both ligands activate the receptor, eliciting openings in quick succession grouped in clusters of high open probability. Mean closed, open and cluster durations remained constant at all agonist concentrations tested. When each ago-PAM was evaluated in the presence of tryptamine (an orthosteric agonist), we observed events with mean open durations similar to those observed in the presence of tryptamine alone, but cluster duration was clearly prolonged probably due to decreased desensitization. These results suggest that the mechanism of activation is governed by the orthosteric agonist while the allosteric drug is only acting as a potentiator. Altogether, our results describe the mechanism underlying human 5-HT3A receptor activation and modulation by two allosteric agonists and provide relevant information for the design of more efficacious and specific drugs.Fil: Rodriguez Araujo, Noelia. 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: Fabiani, Camila. 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; ArgentinaFil: Corradi, Jeremias. 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; ArgentinaXLVII Reunión Anual de la Sociedad Argentina de Biofísica (SAB)La PlataArgentinaSociedad Argentina de BiofísicaXLVII Reunión Anual de la Sociedad Argentina de Biofísica2018info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/conferenceObjectCongresoBookhttp://purl.org/coar/resource_type/c_5794info:ar-repo/semantics/documentoDeConferenciaapplication/pdfapplication/pdfapplication/pdfapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/231789Mechanism of 5-HT3 receptor activation and modulation by allosteric drugs; XLVII Reunión Anual de la Sociedad Argentina de Biofísica (SAB); La Plata; Argentina; 2018; 112-112978-987-27591-6-2CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://biofisica.org.ar/reuniones-cientificas/reunionsab-previas/Nacionalinfo:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-29T09:32:24Zoai:ri.conicet.gov.ar:11336/231789instacron: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 09:32:24.751CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Mechanism of 5-HT3 receptor activation and modulation by allosteric drugs
title Mechanism of 5-HT3 receptor activation and modulation by allosteric drugs
spellingShingle Mechanism of 5-HT3 receptor activation and modulation by allosteric drugs
Rodriguez Araujo, Noelia
SEROTONIN
HETEROMERIC RECEPTORS
PATCH-CLAMP
MODULATION
title_short Mechanism of 5-HT3 receptor activation and modulation by allosteric drugs
title_full Mechanism of 5-HT3 receptor activation and modulation by allosteric drugs
title_fullStr Mechanism of 5-HT3 receptor activation and modulation by allosteric drugs
title_full_unstemmed Mechanism of 5-HT3 receptor activation and modulation by allosteric drugs
title_sort Mechanism of 5-HT3 receptor activation and modulation by allosteric drugs
dc.creator.none.fl_str_mv Rodriguez Araujo, Noelia
Fabiani, Camila
Bouzat, Cecilia Beatriz
Corradi, Jeremias
author Rodriguez Araujo, Noelia
author_facet Rodriguez Araujo, Noelia
Fabiani, Camila
Bouzat, Cecilia Beatriz
Corradi, Jeremias
author_role author
author2 Fabiani, Camila
Bouzat, Cecilia Beatriz
Corradi, Jeremias
author2_role author
author
author
dc.subject.none.fl_str_mv SEROTONIN
HETEROMERIC RECEPTORS
PATCH-CLAMP
MODULATION
topic SEROTONIN
HETEROMERIC RECEPTORS
PATCH-CLAMP
MODULATION
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.6
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv Serotonin type 3 receptors (5-HT3) are cation-selective channels that belong to the Cys-loop receptor family. They are involved in fast excitatory transmission in central and peripheral nervous systems and are implicated in gastrointestinal and neurological functions. Five different subunits (A-E) have been identified in humans, and the A subunit is the only one capable of forming functional homomeric receptors (5-HT3A). These receptors are activated by agonist binding to orthosteric sites located at the interfaces between two adjacent subunits at the extracellular region. Carvacrol and thymol have been classified as positive allosteric modulators that also act as allosteric agonists (ago-PAMs). To characterize their mechanism of activation and modulation we used the high- conductance form of the 5-HT3A receptor that allows detection of single-channel openings from patch-clamp recordings. We observed that both ligands activate the receptor, eliciting openings in quick succession grouped in clusters of high open probability. Mean closed, open and cluster durations remained constant at all agonist concentrations tested. When each ago-PAM was evaluated in the presence of tryptamine (an orthosteric agonist), we observed events with mean open durations similar to those observed in the presence of tryptamine alone, but cluster duration was clearly prolonged probably due to decreased desensitization. These results suggest that the mechanism of activation is governed by the orthosteric agonist while the allosteric drug is only acting as a potentiator. Altogether, our results describe the mechanism underlying human 5-HT3A receptor activation and modulation by two allosteric agonists and provide relevant information for the design of more efficacious and specific drugs.
Fil: Rodriguez Araujo, Noelia. 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: Fabiani, Camila. 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
Fil: Corradi, Jeremias. 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
XLVII Reunión Anual de la Sociedad Argentina de Biofísica (SAB)
La Plata
Argentina
Sociedad Argentina de Biofísica
description Serotonin type 3 receptors (5-HT3) are cation-selective channels that belong to the Cys-loop receptor family. They are involved in fast excitatory transmission in central and peripheral nervous systems and are implicated in gastrointestinal and neurological functions. Five different subunits (A-E) have been identified in humans, and the A subunit is the only one capable of forming functional homomeric receptors (5-HT3A). These receptors are activated by agonist binding to orthosteric sites located at the interfaces between two adjacent subunits at the extracellular region. Carvacrol and thymol have been classified as positive allosteric modulators that also act as allosteric agonists (ago-PAMs). To characterize their mechanism of activation and modulation we used the high- conductance form of the 5-HT3A receptor that allows detection of single-channel openings from patch-clamp recordings. We observed that both ligands activate the receptor, eliciting openings in quick succession grouped in clusters of high open probability. Mean closed, open and cluster durations remained constant at all agonist concentrations tested. When each ago-PAM was evaluated in the presence of tryptamine (an orthosteric agonist), we observed events with mean open durations similar to those observed in the presence of tryptamine alone, but cluster duration was clearly prolonged probably due to decreased desensitization. These results suggest that the mechanism of activation is governed by the orthosteric agonist while the allosteric drug is only acting as a potentiator. Altogether, our results describe the mechanism underlying human 5-HT3A receptor activation and modulation by two allosteric agonists and provide relevant information for the design of more efficacious and specific drugs.
publishDate 2018
dc.date.none.fl_str_mv 2018
dc.type.none.fl_str_mv info:eu-repo/semantics/publishedVersion
info:eu-repo/semantics/conferenceObject
Congreso
Book
http://purl.org/coar/resource_type/c_5794
info:ar-repo/semantics/documentoDeConferencia
status_str publishedVersion
format conferenceObject
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/231789
Mechanism of 5-HT3 receptor activation and modulation by allosteric drugs; XLVII Reunión Anual de la Sociedad Argentina de Biofísica (SAB); La Plata; Argentina; 2018; 112-112
978-987-27591-6-2
CONICET Digital
CONICET
url http://hdl.handle.net/11336/231789
identifier_str_mv Mechanism of 5-HT3 receptor activation and modulation by allosteric drugs; XLVII Reunión Anual de la Sociedad Argentina de Biofísica (SAB); La Plata; Argentina; 2018; 112-112
978-987-27591-6-2
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://biofisica.org.ar/reuniones-cientificas/reunionsab-previas/
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/
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application/pdf
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application/pdf
dc.coverage.none.fl_str_mv Nacional
dc.publisher.none.fl_str_mv XLVII Reunión Anual de la Sociedad Argentina de Biofísica
publisher.none.fl_str_mv XLVII Reunión Anual de la Sociedad Argentina de Biofísica
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
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repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
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