A novel receptor target for old anthelmintic drugs evaluated in the nematode Caenorhabditis elegans

Autores
Rodriguez Araujo, Noelia; Hernando, Guillermina Silvana; Corradi, Jeremias; Bouzat, Cecilia Beatriz
Año de publicación
2021
Idioma
inglés
Tipo de recurso
documento de conferencia
Estado
versión publicada
Descripción
Ivermectin (IVM) and piperazine (PZE), which are agonists of Glutamate-gated chloride channels and GABAA receptors, respectively, are marketed drugs used in anthelmintic therapy. Here we discovered a novel target of these drugs by evaluating their effects on the free-living nematode C. elegans. Nematodes contain a homomeric 5HT-gated chloride channel, MOD-1, that modulates locomotor behavior. Due to its absence in vertebrates, MOD-1 emerges as an attractive anthelmintic drug target. By electrophysiological recordings from cells expressing MOD-1, we deciphered its pharmacological properties and searched for novel ligands. Macroscopic currents activated by 5-HT showed that MOD-1 desensitizes slowly and recovers from desensitization in about 1 s. Dose-response curves revealed an EC50 for 5-HT of ~1 μM, similar to that of 5-HT3A receptors. The partial agonists tryptamine and 2-Me-5HT showed very different efficacies between MOD-1 and 5-HT3A receptors. IVM and PZE did not activate MOD-1 but acted as non-competitive antagonists. IVM produced a slight and irreversible inhibition whereas PZE led to a profound and reversible inhibition, indicating that MOD-1 may be involved in their anthelmintic effects. Also, the specific GABAA receptor agonists, muscimol and isoguvacine, inhibited MOD-1 currents. We performed locomotor activity assays of wild- type (WT) and mutant strains to establish MOD-1 as a novel anthelmintic target. We found that 5-HT produced a rapid paralysis of WT worms while the MOD-1 mutant strain was resistant, thus confirming MOD-1 as the functional target of 5-HT. The exposure of worms to 5-HT combined with IVM or PZE at concentrations at which they do not act at their canonical receptors reduced the 5-HT paralyzing effect, thus supporting the negative modulation of MOD-1 detected in electrophysiological recordings. This study contributes to our understanding of the action of drugs to treat parasitic diseases and to guide future drug discovery efforts.
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: Hernando, Guillermina Silvana. 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
XLIX Reunión Anual de la Sociedad Argentina de Biofísica
Argentina
Sociedad Argentina de Biofísica
Materia
CHLORIDE CHANNEL
ANTHELMINTIC THERAPY
CAENORHABDITIS ELEGANS
DRUG TARGET
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:11336/176090
Acceder
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network_name_str CONICET Digital (CONICET)
spelling A novel receptor target for old anthelmintic drugs evaluated in the nematode Caenorhabditis elegansRodriguez Araujo, NoeliaHernando, Guillermina SilvanaCorradi, JeremiasBouzat, Cecilia BeatrizCHLORIDE CHANNELANTHELMINTIC THERAPYCAENORHABDITIS ELEGANSDRUG TARGEThttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1Ivermectin (IVM) and piperazine (PZE), which are agonists of Glutamate-gated chloride channels and GABAA receptors, respectively, are marketed drugs used in anthelmintic therapy. Here we discovered a novel target of these drugs by evaluating their effects on the free-living nematode C. elegans. Nematodes contain a homomeric 5HT-gated chloride channel, MOD-1, that modulates locomotor behavior. Due to its absence in vertebrates, MOD-1 emerges as an attractive anthelmintic drug target. By electrophysiological recordings from cells expressing MOD-1, we deciphered its pharmacological properties and searched for novel ligands. Macroscopic currents activated by 5-HT showed that MOD-1 desensitizes slowly and recovers from desensitization in about 1 s. Dose-response curves revealed an EC50 for 5-HT of ~1 μM, similar to that of 5-HT3A receptors. The partial agonists tryptamine and 2-Me-5HT showed very different efficacies between MOD-1 and 5-HT3A receptors. IVM and PZE did not activate MOD-1 but acted as non-competitive antagonists. IVM produced a slight and irreversible inhibition whereas PZE led to a profound and reversible inhibition, indicating that MOD-1 may be involved in their anthelmintic effects. Also, the specific GABAA receptor agonists, muscimol and isoguvacine, inhibited MOD-1 currents. We performed locomotor activity assays of wild- type (WT) and mutant strains to establish MOD-1 as a novel anthelmintic target. We found that 5-HT produced a rapid paralysis of WT worms while the MOD-1 mutant strain was resistant, thus confirming MOD-1 as the functional target of 5-HT. The exposure of worms to 5-HT combined with IVM or PZE at concentrations at which they do not act at their canonical receptors reduced the 5-HT paralyzing effect, thus supporting the negative modulation of MOD-1 detected in electrophysiological recordings. This study contributes to our understanding of the action of drugs to treat parasitic diseases and to guide future drug discovery efforts.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: Hernando, Guillermina Silvana. 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; ArgentinaXLIX Reunión Anual de la Sociedad Argentina de BiofísicaArgentinaSociedad 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/vnd.openxmlformats-officedocument.wordprocessingml.documentapplication/pdfhttp://hdl.handle.net/11336/176090A novel receptor target for old anthelmintic drugs evaluated in the nematode Caenorhabditis elegans; XLIX Reunión Anual de la Sociedad Argentina de Biofísica; Argentina; 2021; 71-71978-987-27591-9-3CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://biofisica.org.ar/reuniones-cientificas/reunionsab-previas/Internacionalinfo:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-11-26T09:06:18Zoai:ri.conicet.gov.ar:11336/176090instacron: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:34982025-11-26 09:06:18.358CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv A novel receptor target for old anthelmintic drugs evaluated in the nematode Caenorhabditis elegans
title A novel receptor target for old anthelmintic drugs evaluated in the nematode Caenorhabditis elegans
spellingShingle A novel receptor target for old anthelmintic drugs evaluated in the nematode Caenorhabditis elegans
Rodriguez Araujo, Noelia
CHLORIDE CHANNEL
ANTHELMINTIC THERAPY
CAENORHABDITIS ELEGANS
DRUG TARGET
title_short A novel receptor target for old anthelmintic drugs evaluated in the nematode Caenorhabditis elegans
title_full A novel receptor target for old anthelmintic drugs evaluated in the nematode Caenorhabditis elegans
title_fullStr A novel receptor target for old anthelmintic drugs evaluated in the nematode Caenorhabditis elegans
title_full_unstemmed A novel receptor target for old anthelmintic drugs evaluated in the nematode Caenorhabditis elegans
title_sort A novel receptor target for old anthelmintic drugs evaluated in the nematode Caenorhabditis elegans
dc.creator.none.fl_str_mv Rodriguez Araujo, Noelia
Hernando, Guillermina Silvana
Corradi, Jeremias
Bouzat, Cecilia Beatriz
author Rodriguez Araujo, Noelia
author_facet Rodriguez Araujo, Noelia
Hernando, Guillermina Silvana
Corradi, Jeremias
Bouzat, Cecilia Beatriz
author_role author
author2 Hernando, Guillermina Silvana
Corradi, Jeremias
Bouzat, Cecilia Beatriz
author2_role author
author
author
dc.contributor.none.fl_str_mv Delfino, Jose Maria
dc.subject.none.fl_str_mv CHLORIDE CHANNEL
ANTHELMINTIC THERAPY
CAENORHABDITIS ELEGANS
DRUG TARGET
topic CHLORIDE CHANNEL
ANTHELMINTIC THERAPY
CAENORHABDITIS ELEGANS
DRUG TARGET
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.6
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv Ivermectin (IVM) and piperazine (PZE), which are agonists of Glutamate-gated chloride channels and GABAA receptors, respectively, are marketed drugs used in anthelmintic therapy. Here we discovered a novel target of these drugs by evaluating their effects on the free-living nematode C. elegans. Nematodes contain a homomeric 5HT-gated chloride channel, MOD-1, that modulates locomotor behavior. Due to its absence in vertebrates, MOD-1 emerges as an attractive anthelmintic drug target. By electrophysiological recordings from cells expressing MOD-1, we deciphered its pharmacological properties and searched for novel ligands. Macroscopic currents activated by 5-HT showed that MOD-1 desensitizes slowly and recovers from desensitization in about 1 s. Dose-response curves revealed an EC50 for 5-HT of ~1 μM, similar to that of 5-HT3A receptors. The partial agonists tryptamine and 2-Me-5HT showed very different efficacies between MOD-1 and 5-HT3A receptors. IVM and PZE did not activate MOD-1 but acted as non-competitive antagonists. IVM produced a slight and irreversible inhibition whereas PZE led to a profound and reversible inhibition, indicating that MOD-1 may be involved in their anthelmintic effects. Also, the specific GABAA receptor agonists, muscimol and isoguvacine, inhibited MOD-1 currents. We performed locomotor activity assays of wild- type (WT) and mutant strains to establish MOD-1 as a novel anthelmintic target. We found that 5-HT produced a rapid paralysis of WT worms while the MOD-1 mutant strain was resistant, thus confirming MOD-1 as the functional target of 5-HT. The exposure of worms to 5-HT combined with IVM or PZE at concentrations at which they do not act at their canonical receptors reduced the 5-HT paralyzing effect, thus supporting the negative modulation of MOD-1 detected in electrophysiological recordings. This study contributes to our understanding of the action of drugs to treat parasitic diseases and to guide future drug discovery efforts.
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: Hernando, Guillermina Silvana. 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
XLIX Reunión Anual de la Sociedad Argentina de Biofísica
Argentina
Sociedad Argentina de Biofísica
description Ivermectin (IVM) and piperazine (PZE), which are agonists of Glutamate-gated chloride channels and GABAA receptors, respectively, are marketed drugs used in anthelmintic therapy. Here we discovered a novel target of these drugs by evaluating their effects on the free-living nematode C. elegans. Nematodes contain a homomeric 5HT-gated chloride channel, MOD-1, that modulates locomotor behavior. Due to its absence in vertebrates, MOD-1 emerges as an attractive anthelmintic drug target. By electrophysiological recordings from cells expressing MOD-1, we deciphered its pharmacological properties and searched for novel ligands. Macroscopic currents activated by 5-HT showed that MOD-1 desensitizes slowly and recovers from desensitization in about 1 s. Dose-response curves revealed an EC50 for 5-HT of ~1 μM, similar to that of 5-HT3A receptors. The partial agonists tryptamine and 2-Me-5HT showed very different efficacies between MOD-1 and 5-HT3A receptors. IVM and PZE did not activate MOD-1 but acted as non-competitive antagonists. IVM produced a slight and irreversible inhibition whereas PZE led to a profound and reversible inhibition, indicating that MOD-1 may be involved in their anthelmintic effects. Also, the specific GABAA receptor agonists, muscimol and isoguvacine, inhibited MOD-1 currents. We performed locomotor activity assays of wild- type (WT) and mutant strains to establish MOD-1 as a novel anthelmintic target. We found that 5-HT produced a rapid paralysis of WT worms while the MOD-1 mutant strain was resistant, thus confirming MOD-1 as the functional target of 5-HT. The exposure of worms to 5-HT combined with IVM or PZE at concentrations at which they do not act at their canonical receptors reduced the 5-HT paralyzing effect, thus supporting the negative modulation of MOD-1 detected in electrophysiological recordings. This study contributes to our understanding of the action of drugs to treat parasitic diseases and to guide future drug discovery efforts.
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/11336/176090
A novel receptor target for old anthelmintic drugs evaluated in the nematode Caenorhabditis elegans; XLIX Reunión Anual de la Sociedad Argentina de Biofísica; Argentina; 2021; 71-71
978-987-27591-9-3
CONICET Digital
CONICET
url http://hdl.handle.net/11336/176090
identifier_str_mv A novel receptor target for old anthelmintic drugs evaluated in the nematode Caenorhabditis elegans; XLIX Reunión Anual de la Sociedad Argentina de Biofísica; Argentina; 2021; 71-71
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/reunionsab-previas/
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/vnd.openxmlformats-officedocument.wordprocessingml.document
application/pdf
dc.coverage.none.fl_str_mv Internacional
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)
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repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
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