Molecular pharmacology of 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 syn- aptic transmission. In mammals, 5-HT3 are non-selective cationic channels that can be homomeric (5-HT3 A) or heteromeric. Caenor- habditis elegans is a model for the study of the nervous system and for antiparasitic drug discovery. As parasitic nematodes, C. el- egans contains a homomeric 5HT-gated chloride channel, MOD-1, that modulates locomotory behavior. Due to its absence in verte- brates, 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 heterolo- gously expressing MOD-1. Macroscopic currents activated by 5-HT showed that MOD-1 does not rectify, desensitizes slowly, and re- covers from desensitization with a time constant of 1 s. Dose-re- sponse curves revealed an EC50 for 5-HT of about 1 μM, similar to that of human 5-HT3 A receptors. However, compared to their actions as partial agonists of human 5-HT3 A receptors, tryptamine showed markedly increased efficacy and 2-Me-5HT showed insig- nificant 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 heterologous- ly expressed in mammalian cells. The elucidation of the molecular pharmacology of MOD-1 contributes to our knowledge of the func- tion 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
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: 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
LXV Reunión Anual de la Sociedad Argentina de Investigación Clínica; LXVIII Reunión Anual de Ia Sociedad Argentina de Inmunología y Reunión Anual de la Sociedad Argentina de Fisiología
Argentina
Sociedad Argentina de Investigación Clínica
Sociedad Argentina de Inmunología
Sociedad Argentina de Fisiología
Materia
DRUG THERAPY
NEMATODE
SEROTONIN
CHLORIDE CHANNEL
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:11336/187860
Acceder
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repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Molecular pharmacology of Caenorhabditis elegans serotonin-gated chloride channel mod-1 as a novel drug target for anthelmintic therapyRodriguez Araujo, NoeliaCorradi, JeremiasBouzat, Cecilia BeatrizDRUG THERAPYNEMATODESEROTONINCHLORIDE CHANNELhttps://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 syn- aptic transmission. In mammals, 5-HT3 are non-selective cationic channels that can be homomeric (5-HT3 A) or heteromeric. Caenor- habditis elegans is a model for the study of the nervous system and for antiparasitic drug discovery. As parasitic nematodes, C. el- egans contains a homomeric 5HT-gated chloride channel, MOD-1, that modulates locomotory behavior. Due to its absence in verte- brates, 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 heterolo- gously expressing MOD-1. Macroscopic currents activated by 5-HT showed that MOD-1 does not rectify, desensitizes slowly, and re- covers from desensitization with a time constant of 1 s. Dose-re- sponse curves revealed an EC50 for 5-HT of about 1 μM, similar to that of human 5-HT3 A receptors. However, compared to their actions as partial agonists of human 5-HT3 A receptors, tryptamine showed markedly increased efficacy and 2-Me-5HT showed insig- nificant 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 heterologous- ly expressed in mammalian cells. The elucidation of the molecular pharmacology of MOD-1 contributes to our knowledge of the func- tion 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; 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; 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; ArgentinaLXV Reunión Anual de la Sociedad Argentina de Investigación Clínica; LXVIII Reunión Anual de Ia Sociedad Argentina de Inmunología y Reunión Anual de la Sociedad Argentina de FisiologíaArgentinaSociedad Argentina de Investigación ClínicaSociedad Argentina de InmunologíaSociedad Argentina de FisiologíaFundación Revista Medicina2020info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/conferenceObjectReuniónJournalhttp://purl.org/coar/resource_type/c_5794info:ar-repo/semantics/documentoDeConferenciaapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/187860Molecular pharmacology of Caenorhabditis elegans serotonin-gated chloride channel mod-1 as a novel drug target for anthelmintic therapy; LXV Reunión Anual de la Sociedad Argentina de Investigación Clínica; LXVIII Reunión Anual de Ia Sociedad Argentina de Inmunología y Reunión Anual de la Sociedad Argentina de Fisiología; Argentina; 2020; 65-650025-76801669-9106CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://www.saic.org.ar/revista-medicinaNacionalinfo:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-10-15T15:06:01Zoai:ri.conicet.gov.ar:11336/187860instacron: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:34982025-10-15 15:06:02.032CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Molecular pharmacology of Caenorhabditis elegans serotonin-gated chloride channel mod-1 as a novel drug target for anthelmintic therapy
title Molecular pharmacology of Caenorhabditis elegans serotonin-gated chloride channel mod-1 as a novel drug target for anthelmintic therapy
spellingShingle Molecular pharmacology of Caenorhabditis elegans serotonin-gated chloride channel mod-1 as a novel drug target for anthelmintic therapy
Rodriguez Araujo, Noelia
DRUG THERAPY
NEMATODE
SEROTONIN
CHLORIDE CHANNEL
title_short Molecular pharmacology of Caenorhabditis elegans serotonin-gated chloride channel mod-1 as a novel drug target for anthelmintic therapy
title_full Molecular pharmacology of Caenorhabditis elegans serotonin-gated chloride channel mod-1 as a novel drug target for anthelmintic therapy
title_fullStr Molecular pharmacology of Caenorhabditis elegans serotonin-gated chloride channel mod-1 as a novel drug target for anthelmintic therapy
title_full_unstemmed Molecular pharmacology of Caenorhabditis elegans serotonin-gated chloride channel mod-1 as a novel drug target for anthelmintic therapy
title_sort Molecular pharmacology of 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.subject.none.fl_str_mv DRUG THERAPY
NEMATODE
SEROTONIN
CHLORIDE CHANNEL
topic DRUG THERAPY
NEMATODE
SEROTONIN
CHLORIDE CHANNEL
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 syn- aptic transmission. In mammals, 5-HT3 are non-selective cationic channels that can be homomeric (5-HT3 A) or heteromeric. Caenor- habditis elegans is a model for the study of the nervous system and for antiparasitic drug discovery. As parasitic nematodes, C. el- egans contains a homomeric 5HT-gated chloride channel, MOD-1, that modulates locomotory behavior. Due to its absence in verte- brates, 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 heterolo- gously expressing MOD-1. Macroscopic currents activated by 5-HT showed that MOD-1 does not rectify, desensitizes slowly, and re- covers from desensitization with a time constant of 1 s. Dose-re- sponse curves revealed an EC50 for 5-HT of about 1 μM, similar to that of human 5-HT3 A receptors. However, compared to their actions as partial agonists of human 5-HT3 A receptors, tryptamine showed markedly increased efficacy and 2-Me-5HT showed insig- nificant 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 heterologous- ly expressed in mammalian cells. The elucidation of the molecular pharmacology of MOD-1 contributes to our knowledge of the func- tion 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
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: 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
LXV Reunión Anual de la Sociedad Argentina de Investigación Clínica; LXVIII Reunión Anual de Ia Sociedad Argentina de Inmunología y Reunión Anual de la Sociedad Argentina de Fisiología
Argentina
Sociedad Argentina de Investigación Clínica
Sociedad Argentina de Inmunología
Sociedad Argentina de Fisiología
description Serotonin-gated ion channels (5-HT3 ) belong to the family of Cys- loop receptors, which are pentameric proteins that mediate fast syn- aptic transmission. In mammals, 5-HT3 are non-selective cationic channels that can be homomeric (5-HT3 A) or heteromeric. Caenor- habditis elegans is a model for the study of the nervous system and for antiparasitic drug discovery. As parasitic nematodes, C. el- egans contains a homomeric 5HT-gated chloride channel, MOD-1, that modulates locomotory behavior. Due to its absence in verte- brates, 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 heterolo- gously expressing MOD-1. Macroscopic currents activated by 5-HT showed that MOD-1 does not rectify, desensitizes slowly, and re- covers from desensitization with a time constant of 1 s. Dose-re- sponse curves revealed an EC50 for 5-HT of about 1 μM, similar to that of human 5-HT3 A receptors. However, compared to their actions as partial agonists of human 5-HT3 A receptors, tryptamine showed markedly increased efficacy and 2-Me-5HT showed insig- nificant 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 heterologous- ly expressed in mammalian cells. The elucidation of the molecular pharmacology of MOD-1 contributes to our knowledge of the func- tion 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
Reunión
Journal
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/11336/187860
Molecular pharmacology of Caenorhabditis elegans serotonin-gated chloride channel mod-1 as a novel drug target for anthelmintic therapy; LXV Reunión Anual de la Sociedad Argentina de Investigación Clínica; LXVIII Reunión Anual de Ia Sociedad Argentina de Inmunología y Reunión Anual de la Sociedad Argentina de Fisiología; Argentina; 2020; 65-65
0025-7680
1669-9106
CONICET Digital
CONICET
url http://hdl.handle.net/11336/187860
identifier_str_mv Molecular pharmacology of Caenorhabditis elegans serotonin-gated chloride channel mod-1 as a novel drug target for anthelmintic therapy; LXV Reunión Anual de la Sociedad Argentina de Investigación Clínica; LXVIII Reunión Anual de Ia Sociedad Argentina de Inmunología y Reunión Anual de la Sociedad Argentina de Fisiología; Argentina; 2020; 65-65
0025-7680
1669-9106
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.saic.org.ar/revista-medicina
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dc.coverage.none.fl_str_mv Nacional
dc.publisher.none.fl_str_mv Fundación Revista Medicina
publisher.none.fl_str_mv Fundación Revista Medicina
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
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repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
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