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
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/245456
Acceder
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oai_identifier_str oai:ri.conicet.gov.ar:11336/245456
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling 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 Técnicas2025-09-29T10:29:32Zoai: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:34982025-09-29 10:29:32.932CONICET 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
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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