Caenorhabditis elegans serotonin-gated chloride channel MOD-1 as a novel drug target for anthelmintic therapy

Autores
Rodriguez Araujo, Noelia; Corradi, Jeremias; Bouzat, Cecilia Beatriz
Año de publicación
2020
Idioma
inglés
Tipo de recurso
documento de conferencia
Estado
versión publicada
Descripción
Serotonin-gated ion channels (5-HT3) belong to the family of Cys-loop receptors, which are pentameric proteins that mediate fast synaptic transmission. In mammals, 5-HT3 are non-selective cationic channels that can be homomeric (5-HT3A) or heteromeric. Caenorhabditis elegans is a model for the study of the nervous system and for antiparasitic drug discovery. As parasitic nematodes, C. elegans contains a homomeric 5HT-gated chloride channel, MOD-1, that modulates locomotory behavior. Due to its absence in vertebrates, MOD-1 emerges as a potential antiparasitic drug target. We deciphered its pharmacological properties and searched for novel ligands by patch clamp recordings from mammalian cells heterologously expressing MOD-1. Macroscopic currents activated by 5-HT showed that MOD-1 does not rectify, desensitizes slowly, and recovers from desensitization with a time constant of 1 s. Dose-response curves revealed an EC50 for 5-HT of about 1 µM, similar to that of human 5-HT3A receptors. However, compared to their actions as partial agonists of human 5-HT3A receptors, tryptamine showed markedly increased efficacy and 2-Me-5HT showed insignificant agonist activity at MOD-1. The typical anthelmintic drugs ivermectin (IVM), levamisole, and piperazine, which are agonists of GluCl, L-AChR and GABA receptors, respectively, did not activate MOD-1. However, IVM produced a slight and piperazine a profound inhibition of 5-HT activated MOD-1 currents. The analysis revealed that piperazine is a noncompetitive antagonist of MOD-1. To gain further insights into the molecular function of the native MOD-1, we also recorded 5HT-activated chloride channels from C. elegans neurons expressing MOD-1 and compared to those heterologously expressed in mammalian cells. The elucidation of the molecular pharmacology of MOD-1 contributes to our knowledge of the function and drug selectivity of Cys-loop receptors and to its potential as a novel target for anthelmintic therapy.
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. Universidad Nacional del Sur. Departamento de Biología, Bioquímica y Farmacia; 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. Universidad Nacional del Sur. Departamento de Biología, Bioquímica y Farmacia; 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. Universidad Nacional del Sur. Departamento de Biología, Bioquímica y Farmacia; Argentina
Primeras Jornadas Virtuales de la Sociedad Argentina de Biofísica
Argentina
Sociedad Argentina de Biofísica
Materia
ANTHELMINTIC THERAPY
SEROTONIN-GATED ION CHANNELS
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:11336/161887
Acceder
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network_acronym_str CONICETDig
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network_name_str CONICET Digital (CONICET)
spelling Caenorhabditis elegans serotonin-gated chloride channel MOD-1 as a novel drug target for anthelmintic therapyRodriguez Araujo, NoeliaCorradi, JeremiasBouzat, Cecilia BeatrizANTHELMINTIC THERAPYSEROTONIN-GATED ION CHANNELShttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1Serotonin-gated ion channels (5-HT3) belong to the family of Cys-loop receptors, which are pentameric proteins that mediate fast synaptic transmission. In mammals, 5-HT3 are non-selective cationic channels that can be homomeric (5-HT3A) or heteromeric. Caenorhabditis elegans is a model for the study of the nervous system and for antiparasitic drug discovery. As parasitic nematodes, C. elegans contains a homomeric 5HT-gated chloride channel, MOD-1, that modulates locomotory behavior. Due to its absence in vertebrates, MOD-1 emerges as a potential antiparasitic drug target. We deciphered its pharmacological properties and searched for novel ligands by patch clamp recordings from mammalian cells heterologously expressing MOD-1. Macroscopic currents activated by 5-HT showed that MOD-1 does not rectify, desensitizes slowly, and recovers from desensitization with a time constant of 1 s. Dose-response curves revealed an EC50 for 5-HT of about 1 µM, similar to that of human 5-HT3A receptors. However, compared to their actions as partial agonists of human 5-HT3A receptors, tryptamine showed markedly increased efficacy and 2-Me-5HT showed insignificant agonist activity at MOD-1. The typical anthelmintic drugs ivermectin (IVM), levamisole, and piperazine, which are agonists of GluCl, L-AChR and GABA receptors, respectively, did not activate MOD-1. However, IVM produced a slight and piperazine a profound inhibition of 5-HT activated MOD-1 currents. The analysis revealed that piperazine is a noncompetitive antagonist of MOD-1. To gain further insights into the molecular function of the native MOD-1, we also recorded 5HT-activated chloride channels from C. elegans neurons expressing MOD-1 and compared to those heterologously expressed in mammalian cells. The elucidation of the molecular pharmacology of MOD-1 contributes to our knowledge of the function and drug selectivity of Cys-loop receptors and to its potential as a novel target for anthelmintic therapy.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. Universidad Nacional del Sur. Departamento de Biología, Bioquímica y Farmacia; 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; Argentina. Universidad Nacional del Sur. Departamento de Biología, Bioquímica y Farmacia; 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; Argentina. Universidad Nacional del Sur. Departamento de Biología, Bioquímica y Farmacia; ArgentinaPrimeras Jornadas Virtuales de la Sociedad Argentina de BiofísicaArgentinaSociedad Argentina de BiofísicaSociedad Argentina de BiofísicaDelofino, Jose M.2020info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/conferenceObjectJornadaBookhttp://purl.org/coar/resource_type/c_5794info:ar-repo/semantics/documentoDeConferenciaapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/161887Caenorhabditis elegans serotonin-gated chloride channel MOD-1 as a novel drug target for anthelmintic therapy; Primeras Jornadas Virtuales de la Sociedad Argentina de Biofísica; Argentina; 2020; 48-48978-987-27591-8-6CONICET 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 Técnicas2025-11-05T09:50:40Zoai:ri.conicet.gov.ar:11336/161887instacron: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:34982025-11-05 09:50:40.923CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Caenorhabditis elegans serotonin-gated chloride channel MOD-1 as a novel drug target for anthelmintic therapy
title Caenorhabditis elegans serotonin-gated chloride channel MOD-1 as a novel drug target for anthelmintic therapy
spellingShingle Caenorhabditis elegans serotonin-gated chloride channel MOD-1 as a novel drug target for anthelmintic therapy
Rodriguez Araujo, Noelia
ANTHELMINTIC THERAPY
SEROTONIN-GATED ION CHANNELS
title_short Caenorhabditis elegans serotonin-gated chloride channel MOD-1 as a novel drug target for anthelmintic therapy
title_full Caenorhabditis elegans serotonin-gated chloride channel MOD-1 as a novel drug target for anthelmintic therapy
title_fullStr Caenorhabditis elegans serotonin-gated chloride channel MOD-1 as a novel drug target for anthelmintic therapy
title_full_unstemmed Caenorhabditis elegans serotonin-gated chloride channel MOD-1 as a novel drug target for anthelmintic therapy
title_sort Caenorhabditis elegans serotonin-gated chloride channel MOD-1 as a novel drug target for anthelmintic therapy
dc.creator.none.fl_str_mv Rodriguez Araujo, Noelia
Corradi, Jeremias
Bouzat, Cecilia Beatriz
author Rodriguez Araujo, Noelia
author_facet Rodriguez Araujo, Noelia
Corradi, Jeremias
Bouzat, Cecilia Beatriz
author_role author
author2 Corradi, Jeremias
Bouzat, Cecilia Beatriz
author2_role author
author
dc.contributor.none.fl_str_mv Delofino, Jose M.
dc.subject.none.fl_str_mv ANTHELMINTIC THERAPY
SEROTONIN-GATED ION CHANNELS
topic ANTHELMINTIC THERAPY
SEROTONIN-GATED ION CHANNELS
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-gated ion channels (5-HT3) belong to the family of Cys-loop receptors, which are pentameric proteins that mediate fast synaptic transmission. In mammals, 5-HT3 are non-selective cationic channels that can be homomeric (5-HT3A) or heteromeric. Caenorhabditis elegans is a model for the study of the nervous system and for antiparasitic drug discovery. As parasitic nematodes, C. elegans contains a homomeric 5HT-gated chloride channel, MOD-1, that modulates locomotory behavior. Due to its absence in vertebrates, MOD-1 emerges as a potential antiparasitic drug target. We deciphered its pharmacological properties and searched for novel ligands by patch clamp recordings from mammalian cells heterologously expressing MOD-1. Macroscopic currents activated by 5-HT showed that MOD-1 does not rectify, desensitizes slowly, and recovers from desensitization with a time constant of 1 s. Dose-response curves revealed an EC50 for 5-HT of about 1 µM, similar to that of human 5-HT3A receptors. However, compared to their actions as partial agonists of human 5-HT3A receptors, tryptamine showed markedly increased efficacy and 2-Me-5HT showed insignificant agonist activity at MOD-1. The typical anthelmintic drugs ivermectin (IVM), levamisole, and piperazine, which are agonists of GluCl, L-AChR and GABA receptors, respectively, did not activate MOD-1. However, IVM produced a slight and piperazine a profound inhibition of 5-HT activated MOD-1 currents. The analysis revealed that piperazine is a noncompetitive antagonist of MOD-1. To gain further insights into the molecular function of the native MOD-1, we also recorded 5HT-activated chloride channels from C. elegans neurons expressing MOD-1 and compared to those heterologously expressed in mammalian cells. The elucidation of the molecular pharmacology of MOD-1 contributes to our knowledge of the function and drug selectivity of Cys-loop receptors and to its potential as a novel target for anthelmintic therapy.
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. Universidad Nacional del Sur. Departamento de Biología, Bioquímica y Farmacia; 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. Universidad Nacional del Sur. Departamento de Biología, Bioquímica y Farmacia; 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. Universidad Nacional del Sur. Departamento de Biología, Bioquímica y Farmacia; Argentina
Primeras Jornadas Virtuales de la Sociedad Argentina de Biofísica
Argentina
Sociedad Argentina de Biofísica
description Serotonin-gated ion channels (5-HT3) belong to the family of Cys-loop receptors, which are pentameric proteins that mediate fast synaptic transmission. In mammals, 5-HT3 are non-selective cationic channels that can be homomeric (5-HT3A) or heteromeric. Caenorhabditis elegans is a model for the study of the nervous system and for antiparasitic drug discovery. As parasitic nematodes, C. elegans contains a homomeric 5HT-gated chloride channel, MOD-1, that modulates locomotory behavior. Due to its absence in vertebrates, MOD-1 emerges as a potential antiparasitic drug target. We deciphered its pharmacological properties and searched for novel ligands by patch clamp recordings from mammalian cells heterologously expressing MOD-1. Macroscopic currents activated by 5-HT showed that MOD-1 does not rectify, desensitizes slowly, and recovers from desensitization with a time constant of 1 s. Dose-response curves revealed an EC50 for 5-HT of about 1 µM, similar to that of human 5-HT3A receptors. However, compared to their actions as partial agonists of human 5-HT3A receptors, tryptamine showed markedly increased efficacy and 2-Me-5HT showed insignificant agonist activity at MOD-1. The typical anthelmintic drugs ivermectin (IVM), levamisole, and piperazine, which are agonists of GluCl, L-AChR and GABA receptors, respectively, did not activate MOD-1. However, IVM produced a slight and piperazine a profound inhibition of 5-HT activated MOD-1 currents. The analysis revealed that piperazine is a noncompetitive antagonist of MOD-1. To gain further insights into the molecular function of the native MOD-1, we also recorded 5HT-activated chloride channels from C. elegans neurons expressing MOD-1 and compared to those heterologously expressed in mammalian cells. The elucidation of the molecular pharmacology of MOD-1 contributes to our knowledge of the function and drug selectivity of Cys-loop receptors and to its potential as a novel target for anthelmintic therapy.
publishDate 2020
dc.date.none.fl_str_mv 2020
dc.type.none.fl_str_mv info:eu-repo/semantics/publishedVersion
info:eu-repo/semantics/conferenceObject
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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/11336/161887
Caenorhabditis elegans serotonin-gated chloride channel MOD-1 as a novel drug target for anthelmintic therapy; Primeras Jornadas Virtuales de la Sociedad Argentina de Biofísica; Argentina; 2020; 48-48
978-987-27591-8-6
CONICET Digital
CONICET
url http://hdl.handle.net/11336/161887
identifier_str_mv Caenorhabditis elegans serotonin-gated chloride channel MOD-1 as a novel drug target for anthelmintic therapy; Primeras Jornadas Virtuales de la Sociedad Argentina de Biofísica; Argentina; 2020; 48-48
978-987-27591-8-6
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/
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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
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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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