Differential functional properties between homeoric and heteromeric 5-HT3 receptors

Autores
Mazzarini Dimarco, Albano; Rodriguez Araujo, Noelia; Bouzat, Cecilia Beatriz; Corradi, Jeremias
Año de publicación
2021
Idioma
inglés
Tipo de recurso
documento de conferencia
Estado
versión publicada
Descripción
The serotonin type 3 receptor (5-HT3) is a ligand-gated ion channel that converts the binding of serotonin (5-HT) into a transient cation current and mediates fast excitatory responses in peripheral and central nervous systems. Five human subunits (A-E) have been identified to date, of which only the A subunit can form homomeric receptors (5- HT3A). We performed single-channel and macroscopic current recordings from cells expressing different subunit combinations to determine how the accessory subunits (B-E) contribute to the receptor functional properties. The incorporation of the B subunit increased about 5-fold the EC50 value of 5-HT responses with respect to 5-HT3A receptors. At the single-channel level, 5HT3A receptors cannot be studied due to their reduced conductance. Thus, we also used a high-conductance A subunit (AHC) that forms channels of about 4.5 pA, with openings grouped in long activation episodes of 287 ± 123 ms (-70 mV). The heteromeric 5-HT3AB channel showed reduced amplitude (about 2.0 pA) and briefer activation episodes with respect to the homomeric receptor (47.1 ± 4.4 ms). The pattern of channel activation did not show a clear 5-HT concentration dependence for 5HT3A and 5HT3AB receptors. Also, both receptors were activated and potentiated by the allosteric agonist carvacrol. Expression of AHC with C, D or E subunits showed opening events of different amplitudes, indicating that A can assemble with one of these accessory subunits. However, the frequency of opening was very low, suggesting that more complex subunit arrangements may occur. Molecular docking studies provided insights into how the different accessory subunits may contribute to the binding site. This study provides information required for identifying functional heteromeric receptors in native cells and for understanding their distinct roles and opens doors for the development of specific ligands.
Fil: Mazzarini Dimarco, Albano. 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: 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: 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
XLIX Reunión Anual de la Sociedad Argentina de Biofísica
Reunión Virtual
Argentina
Sociedad Argentina de Biofísica
Materia
HOMOERIC RECEPTORS
HETEROMERIC RECEPTORS
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:11336/161150
Acceder
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network_name_str CONICET Digital (CONICET)
spelling Differential functional properties between homeoric and heteromeric 5-HT3 receptorsMazzarini Dimarco, AlbanoRodriguez Araujo, NoeliaBouzat, Cecilia BeatrizCorradi, JeremiasHOMOERIC RECEPTORSHETEROMERIC RECEPTORShttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1The serotonin type 3 receptor (5-HT3) is a ligand-gated ion channel that converts the binding of serotonin (5-HT) into a transient cation current and mediates fast excitatory responses in peripheral and central nervous systems. Five human subunits (A-E) have been identified to date, of which only the A subunit can form homomeric receptors (5- HT3A). We performed single-channel and macroscopic current recordings from cells expressing different subunit combinations to determine how the accessory subunits (B-E) contribute to the receptor functional properties. The incorporation of the B subunit increased about 5-fold the EC50 value of 5-HT responses with respect to 5-HT3A receptors. At the single-channel level, 5HT3A receptors cannot be studied due to their reduced conductance. Thus, we also used a high-conductance A subunit (AHC) that forms channels of about 4.5 pA, with openings grouped in long activation episodes of 287 ± 123 ms (-70 mV). The heteromeric 5-HT3AB channel showed reduced amplitude (about 2.0 pA) and briefer activation episodes with respect to the homomeric receptor (47.1 ± 4.4 ms). The pattern of channel activation did not show a clear 5-HT concentration dependence for 5HT3A and 5HT3AB receptors. Also, both receptors were activated and potentiated by the allosteric agonist carvacrol. Expression of AHC with C, D or E subunits showed opening events of different amplitudes, indicating that A can assemble with one of these accessory subunits. However, the frequency of opening was very low, suggesting that more complex subunit arrangements may occur. Molecular docking studies provided insights into how the different accessory subunits may contribute to the binding site. This study provides information required for identifying functional heteromeric receptors in native cells and for understanding their distinct roles and opens doors for the development of specific ligands.Fil: Mazzarini Dimarco, Albano. 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: 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: 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; ArgentinaXLIX Reunión Anual de la Sociedad Argentina de BiofísicaReunión VirtualArgentinaSociedad Argentina de BiofísicaSociedad Argentina de BiofísicaDelfino, Jose Maria2021info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/conferenceObjectReuniónBookhttp://purl.org/coar/resource_type/c_5794info:ar-repo/semantics/documentoDeConferenciaapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/161150Differential functional properties between homeoric and heteromeric 5-HT3 receptors; XLIX Reunión Anual de la Sociedad Argentina de Biofísica; Reunión Virtual; Argentina; 2021; 67-67978-987-27591-9-3CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://biofisica.org.ar/reuniones-cientificasNacionalinfo:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-03T09:44:07Zoai:ri.conicet.gov.ar:11336/161150instacron: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 09:44:07.782CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Differential functional properties between homeoric and heteromeric 5-HT3 receptors
title Differential functional properties between homeoric and heteromeric 5-HT3 receptors
spellingShingle Differential functional properties between homeoric and heteromeric 5-HT3 receptors
Mazzarini Dimarco, Albano
HOMOERIC RECEPTORS
HETEROMERIC RECEPTORS
title_short Differential functional properties between homeoric and heteromeric 5-HT3 receptors
title_full Differential functional properties between homeoric and heteromeric 5-HT3 receptors
title_fullStr Differential functional properties between homeoric and heteromeric 5-HT3 receptors
title_full_unstemmed Differential functional properties between homeoric and heteromeric 5-HT3 receptors
title_sort Differential functional properties between homeoric and heteromeric 5-HT3 receptors
dc.creator.none.fl_str_mv Mazzarini Dimarco, Albano
Rodriguez Araujo, Noelia
Bouzat, Cecilia Beatriz
Corradi, Jeremias
author Mazzarini Dimarco, Albano
author_facet Mazzarini Dimarco, Albano
Rodriguez Araujo, Noelia
Bouzat, Cecilia Beatriz
Corradi, Jeremias
author_role author
author2 Rodriguez Araujo, Noelia
Bouzat, Cecilia Beatriz
Corradi, Jeremias
author2_role author
author
author
dc.contributor.none.fl_str_mv Delfino, Jose Maria
dc.subject.none.fl_str_mv HOMOERIC RECEPTORS
HETEROMERIC RECEPTORS
topic HOMOERIC RECEPTORS
HETEROMERIC RECEPTORS
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 serotonin type 3 receptor (5-HT3) is a ligand-gated ion channel that converts the binding of serotonin (5-HT) into a transient cation current and mediates fast excitatory responses in peripheral and central nervous systems. Five human subunits (A-E) have been identified to date, of which only the A subunit can form homomeric receptors (5- HT3A). We performed single-channel and macroscopic current recordings from cells expressing different subunit combinations to determine how the accessory subunits (B-E) contribute to the receptor functional properties. The incorporation of the B subunit increased about 5-fold the EC50 value of 5-HT responses with respect to 5-HT3A receptors. At the single-channel level, 5HT3A receptors cannot be studied due to their reduced conductance. Thus, we also used a high-conductance A subunit (AHC) that forms channels of about 4.5 pA, with openings grouped in long activation episodes of 287 ± 123 ms (-70 mV). The heteromeric 5-HT3AB channel showed reduced amplitude (about 2.0 pA) and briefer activation episodes with respect to the homomeric receptor (47.1 ± 4.4 ms). The pattern of channel activation did not show a clear 5-HT concentration dependence for 5HT3A and 5HT3AB receptors. Also, both receptors were activated and potentiated by the allosteric agonist carvacrol. Expression of AHC with C, D or E subunits showed opening events of different amplitudes, indicating that A can assemble with one of these accessory subunits. However, the frequency of opening was very low, suggesting that more complex subunit arrangements may occur. Molecular docking studies provided insights into how the different accessory subunits may contribute to the binding site. This study provides information required for identifying functional heteromeric receptors in native cells and for understanding their distinct roles and opens doors for the development of specific ligands.
Fil: Mazzarini Dimarco, Albano. 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: 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: 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
XLIX Reunión Anual de la Sociedad Argentina de Biofísica
Reunión Virtual
Argentina
Sociedad Argentina de Biofísica
description The serotonin type 3 receptor (5-HT3) is a ligand-gated ion channel that converts the binding of serotonin (5-HT) into a transient cation current and mediates fast excitatory responses in peripheral and central nervous systems. Five human subunits (A-E) have been identified to date, of which only the A subunit can form homomeric receptors (5- HT3A). We performed single-channel and macroscopic current recordings from cells expressing different subunit combinations to determine how the accessory subunits (B-E) contribute to the receptor functional properties. The incorporation of the B subunit increased about 5-fold the EC50 value of 5-HT responses with respect to 5-HT3A receptors. At the single-channel level, 5HT3A receptors cannot be studied due to their reduced conductance. Thus, we also used a high-conductance A subunit (AHC) that forms channels of about 4.5 pA, with openings grouped in long activation episodes of 287 ± 123 ms (-70 mV). The heteromeric 5-HT3AB channel showed reduced amplitude (about 2.0 pA) and briefer activation episodes with respect to the homomeric receptor (47.1 ± 4.4 ms). The pattern of channel activation did not show a clear 5-HT concentration dependence for 5HT3A and 5HT3AB receptors. Also, both receptors were activated and potentiated by the allosteric agonist carvacrol. Expression of AHC with C, D or E subunits showed opening events of different amplitudes, indicating that A can assemble with one of these accessory subunits. However, the frequency of opening was very low, suggesting that more complex subunit arrangements may occur. Molecular docking studies provided insights into how the different accessory subunits may contribute to the binding site. This study provides information required for identifying functional heteromeric receptors in native cells and for understanding their distinct roles and opens doors for the development of specific ligands.
publishDate 2021
dc.date.none.fl_str_mv 2021
dc.type.none.fl_str_mv info:eu-repo/semantics/publishedVersion
info:eu-repo/semantics/conferenceObject
Reunión
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/11336/161150
Differential functional properties between homeoric and heteromeric 5-HT3 receptors; XLIX Reunión Anual de la Sociedad Argentina de Biofísica; Reunión Virtual; Argentina; 2021; 67-67
978-987-27591-9-3
CONICET Digital
CONICET
url http://hdl.handle.net/11336/161150
identifier_str_mv Differential functional properties between homeoric and heteromeric 5-HT3 receptors; XLIX Reunión Anual de la Sociedad Argentina de Biofísica; Reunión Virtual; Argentina; 2021; 67-67
978-987-27591-9-3
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
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 Biofísica
publisher.none.fl_str_mv Sociedad Argentina de Biofísica
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str CONICET Digital (CONICET)
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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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