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
- Institución
- Consejo Nacional de Investigaciones Científicas y Técnicas
- OAI Identificador
- oai:ri.conicet.gov.ar:11336/231789
Ver los metadatos del registro completo
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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 Técnicas2025-09-03T09:43:19Zoai: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:34982025-09-03 09:43:19.368CONICET 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 |
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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 |
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XLVII Reunión Anual de la Sociedad Argentina de Biofísica |
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XLVII Reunión Anual de la Sociedad Argentina de Biofísica |
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