Kinetic Scheme for Activation and Desensitization of Homomeric 5-HT3A Receptor.
- Autores
- Corradi, Jeremias; Gumilar, Fernanda Andrea; Bouzat, Cecilia Beatriz
- Año de publicación
- 2009
- Idioma
- inglés
- Tipo de recurso
- documento de conferencia
- Estado
- versión publicada
- Descripción
- The 5-HT3A receptor is a member of the Cys-loop family of ligand-gated ion channels. To perform kinetic analysis, we introduced the mutations R432Q/R436D/R440A in the 5-HT3A subunit to obtain a high-conductance form (5-HT3A-HC), in which single-channel currents can be detected. At all 5-HT concentrations (0.1 µM) channel activity appears as openings of ~4.7 pA (-70 mV) in quick succession forming bursts, which coalesce into clusters. By combining single-channel and macroscopic data we generated a kinetic model that perfectly describes activation, deactivation and desensitization. The model shows that full activation arises from receptors with three molecules of agonist bound. It also reveals an earlier conformational change of the fully-liganded receptor that occurs while the channel is still closed. From this pre-open closed state the receptor enters into an open-closed cycle involving three open states, which conforms the cluster whose duration parallels the time constant of desensitization. This suggests that at a synapse the lifetime of the elementary response of 5-HT3A receptors is determined mainly by desensitization. Since the desensitized state is a stable state, the interresponse latency is expected to be prolonged. A similar model but lacking the pre-open closed state can describe the data only if the opening rates are fixed to account for the slow activation rate. Thus, our kinetic model provides a foundation for studying structure-function relationships as well as molecular mechanisms of drug action in 5-HT3 receptors
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
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
First Joint Meeting of the Argentine Society for Neurosciences and the Argentine Workshop in Neurosciences
Huerta Grande
Argentina
Sociedad Argentina de Neurociencias - Materia
-
SEROTONIN
CYS-LOOP
RECEPTORS
PATCH-CLAMP - 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:11336/245456
Ver los metadatos del registro completo
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Kinetic Scheme for Activation and Desensitization of Homomeric 5-HT3A Receptor.Corradi, JeremiasGumilar, Fernanda AndreaBouzat, Cecilia BeatrizSEROTONINCYS-LOOPRECEPTORSPATCH-CLAMPhttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1The 5-HT3A receptor is a member of the Cys-loop family of ligand-gated ion channels. To perform kinetic analysis, we introduced the mutations R432Q/R436D/R440A in the 5-HT3A subunit to obtain a high-conductance form (5-HT3A-HC), in which single-channel currents can be detected. At all 5-HT concentrations (0.1 µM) channel activity appears as openings of ~4.7 pA (-70 mV) in quick succession forming bursts, which coalesce into clusters. By combining single-channel and macroscopic data we generated a kinetic model that perfectly describes activation, deactivation and desensitization. The model shows that full activation arises from receptors with three molecules of agonist bound. It also reveals an earlier conformational change of the fully-liganded receptor that occurs while the channel is still closed. From this pre-open closed state the receptor enters into an open-closed cycle involving three open states, which conforms the cluster whose duration parallels the time constant of desensitization. This suggests that at a synapse the lifetime of the elementary response of 5-HT3A receptors is determined mainly by desensitization. Since the desensitized state is a stable state, the interresponse latency is expected to be prolonged. A similar model but lacking the pre-open closed state can describe the data only if the opening rates are fixed to account for the slow activation rate. Thus, our kinetic model provides a foundation for studying structure-function relationships as well as molecular mechanisms of drug action in 5-HT3 receptorsFil: 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; ArgentinaFil: 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; ArgentinaFirst Joint Meeting of the Argentine Society for Neurosciences and the Argentine Workshop in NeurosciencesHuerta GrandeArgentinaSociedad Argentina de NeurocienciasSociedad Argentina de Investigación en Neurociencias2009info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/conferenceObjectCongresoBookhttp://purl.org/coar/resource_type/c_5794info:ar-repo/semantics/documentoDeConferenciaapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/245456Kinetic Scheme for Activation and Desensitization of Homomeric 5-HT3A Receptor.; First Joint Meeting of the Argentine Society for Neurosciences and the Argentine Workshop in Neurosciences; Huerta Grande; Argentina; 2009; 269-269CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://www.saneurociencias.org.ar/wp-content/uploads/downloads/2012/12/congreso-conjunto-SAN-Taller-2009.pdfNacionalinfo:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-03T10:06:16Zoai:ri.conicet.gov.ar:11336/245456instacron: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 10:06:17.14CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse |
dc.title.none.fl_str_mv |
Kinetic Scheme for Activation and Desensitization of Homomeric 5-HT3A Receptor. |
title |
Kinetic Scheme for Activation and Desensitization of Homomeric 5-HT3A Receptor. |
spellingShingle |
Kinetic Scheme for Activation and Desensitization of Homomeric 5-HT3A Receptor. Corradi, Jeremias SEROTONIN CYS-LOOP RECEPTORS PATCH-CLAMP |
title_short |
Kinetic Scheme for Activation and Desensitization of Homomeric 5-HT3A Receptor. |
title_full |
Kinetic Scheme for Activation and Desensitization of Homomeric 5-HT3A Receptor. |
title_fullStr |
Kinetic Scheme for Activation and Desensitization of Homomeric 5-HT3A Receptor. |
title_full_unstemmed |
Kinetic Scheme for Activation and Desensitization of Homomeric 5-HT3A Receptor. |
title_sort |
Kinetic Scheme for Activation and Desensitization of Homomeric 5-HT3A Receptor. |
dc.creator.none.fl_str_mv |
Corradi, Jeremias Gumilar, Fernanda Andrea Bouzat, Cecilia Beatriz |
author |
Corradi, Jeremias |
author_facet |
Corradi, Jeremias Gumilar, Fernanda Andrea Bouzat, Cecilia Beatriz |
author_role |
author |
author2 |
Gumilar, Fernanda Andrea Bouzat, Cecilia Beatriz |
author2_role |
author author |
dc.subject.none.fl_str_mv |
SEROTONIN CYS-LOOP RECEPTORS PATCH-CLAMP |
topic |
SEROTONIN CYS-LOOP RECEPTORS PATCH-CLAMP |
purl_subject.fl_str_mv |
https://purl.org/becyt/ford/1.6 https://purl.org/becyt/ford/1 |
dc.description.none.fl_txt_mv |
The 5-HT3A receptor is a member of the Cys-loop family of ligand-gated ion channels. To perform kinetic analysis, we introduced the mutations R432Q/R436D/R440A in the 5-HT3A subunit to obtain a high-conductance form (5-HT3A-HC), in which single-channel currents can be detected. At all 5-HT concentrations (0.1 µM) channel activity appears as openings of ~4.7 pA (-70 mV) in quick succession forming bursts, which coalesce into clusters. By combining single-channel and macroscopic data we generated a kinetic model that perfectly describes activation, deactivation and desensitization. The model shows that full activation arises from receptors with three molecules of agonist bound. It also reveals an earlier conformational change of the fully-liganded receptor that occurs while the channel is still closed. From this pre-open closed state the receptor enters into an open-closed cycle involving three open states, which conforms the cluster whose duration parallels the time constant of desensitization. This suggests that at a synapse the lifetime of the elementary response of 5-HT3A receptors is determined mainly by desensitization. Since the desensitized state is a stable state, the interresponse latency is expected to be prolonged. A similar model but lacking the pre-open closed state can describe the data only if the opening rates are fixed to account for the slow activation rate. Thus, our kinetic model provides a foundation for studying structure-function relationships as well as molecular mechanisms of drug action in 5-HT3 receptors 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 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 First Joint Meeting of the Argentine Society for Neurosciences and the Argentine Workshop in Neurosciences Huerta Grande Argentina Sociedad Argentina de Neurociencias |
description |
The 5-HT3A receptor is a member of the Cys-loop family of ligand-gated ion channels. To perform kinetic analysis, we introduced the mutations R432Q/R436D/R440A in the 5-HT3A subunit to obtain a high-conductance form (5-HT3A-HC), in which single-channel currents can be detected. At all 5-HT concentrations (0.1 µM) channel activity appears as openings of ~4.7 pA (-70 mV) in quick succession forming bursts, which coalesce into clusters. By combining single-channel and macroscopic data we generated a kinetic model that perfectly describes activation, deactivation and desensitization. The model shows that full activation arises from receptors with three molecules of agonist bound. It also reveals an earlier conformational change of the fully-liganded receptor that occurs while the channel is still closed. From this pre-open closed state the receptor enters into an open-closed cycle involving three open states, which conforms the cluster whose duration parallels the time constant of desensitization. This suggests that at a synapse the lifetime of the elementary response of 5-HT3A receptors is determined mainly by desensitization. Since the desensitized state is a stable state, the interresponse latency is expected to be prolonged. A similar model but lacking the pre-open closed state can describe the data only if the opening rates are fixed to account for the slow activation rate. Thus, our kinetic model provides a foundation for studying structure-function relationships as well as molecular mechanisms of drug action in 5-HT3 receptors |
publishDate |
2009 |
dc.date.none.fl_str_mv |
2009 |
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/11336/245456 Kinetic Scheme for Activation and Desensitization of Homomeric 5-HT3A Receptor.; First Joint Meeting of the Argentine Society for Neurosciences and the Argentine Workshop in Neurosciences; Huerta Grande; Argentina; 2009; 269-269 CONICET Digital CONICET |
url |
http://hdl.handle.net/11336/245456 |
identifier_str_mv |
Kinetic Scheme for Activation and Desensitization of Homomeric 5-HT3A Receptor.; First Joint Meeting of the Argentine Society for Neurosciences and the Argentine Workshop in Neurosciences; Huerta Grande; Argentina; 2009; 269-269 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.saneurociencias.org.ar/wp-content/uploads/downloads/2012/12/congreso-conjunto-SAN-Taller-2009.pdf |
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 |
dc.coverage.none.fl_str_mv |
Nacional |
dc.publisher.none.fl_str_mv |
Sociedad Argentina de Investigación en Neurociencias |
publisher.none.fl_str_mv |
Sociedad Argentina de Investigación en Neurociencias |
dc.source.none.fl_str_mv |
reponame:CONICET Digital (CONICET) instname:Consejo Nacional de Investigaciones Científicas y Técnicas |
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CONICET Digital (CONICET) |
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CONICET Digital (CONICET) |
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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 |