The antiparasitic bephenium is a potent agonist of Caenorhabditis elegans levamisole-sensitive nicotinic receptors
- Autores
- Turani, Ornella; Hernando, Guillermina Silvana; Corradi, Jeremias; Bouzat, Cecilia Beatriz
- Año de publicación
- 2018
- Idioma
- inglés
- Tipo de recurso
- documento de conferencia
- Estado
- versión publicada
- Descripción
- Nicotinic acetylcholine receptors (nAChRs) are ligand-gated ion channels involved in neuromuscular transmission. In nematodes, muscle nAChRs are main targets of antiparasitic drugs. Nematode parasites contain three pharmacological classes of muscle nAChRs, which are activated by levamisole (L-type), nicotine (N-type) and bephenium (B-type). The free-living nematode Caenorhabditis elegans is a model of parasitic nematodes, useful for drug discovery. Because in C. elegans muscle only the N-AChR and L-AChR classes have been described, we explored the behavioral (by paralysis assays) and molecular actions (by patch clamp recordings) of the antiparasitic bephenium. As in parasites, bephenium produced spastic paralysis. A mutant strain lacking the L-AChR showed full resistance to bephenium, indicating that this receptor is the drug target. Bephenium activated L-AChRs from isolated larvae muscle cells, eliciting channel activity as that elicited by levamisole. The analysis revealed that it is a potent agonist of the L-AChR and an open-channel blocker at higher concentrations. In contrast, we demonstrated that it is a very low efficacious agonist of the mammalian muscle nAChR. Molecular docking studies proposed that bephenium can form key interactions required for activation in mammalian and nematode nAChRs, revealed differences with ACh binding, and provided explanations for the experimental results.
Fil: Turani, Ornella. 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: 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
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
6th International Iberian Biophysics Congress and X Iberoamerican Congress of Biophysics
Castellon
España
Sociedad de Biofísica de España - Materia
-
CAENORHABDITIS ELEGANS
CYS-LOOP RECEPTORS
BEPHENIUM
ANTHELMINTICS - Nivel de accesibilidad
- acceso abierto
- Condiciones de uso
- https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
- Repositorio
- Institución
- Consejo Nacional de Investigaciones Científicas y Técnicas
- OAI Identificador
- oai:ri.conicet.gov.ar:11336/231622
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The antiparasitic bephenium is a potent agonist of Caenorhabditis elegans levamisole-sensitive nicotinic receptorsTurani, OrnellaHernando, Guillermina SilvanaCorradi, JeremiasBouzat, Cecilia BeatrizCAENORHABDITIS ELEGANSCYS-LOOP RECEPTORSBEPHENIUMANTHELMINTICShttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1Nicotinic acetylcholine receptors (nAChRs) are ligand-gated ion channels involved in neuromuscular transmission. In nematodes, muscle nAChRs are main targets of antiparasitic drugs. Nematode parasites contain three pharmacological classes of muscle nAChRs, which are activated by levamisole (L-type), nicotine (N-type) and bephenium (B-type). The free-living nematode Caenorhabditis elegans is a model of parasitic nematodes, useful for drug discovery. Because in C. elegans muscle only the N-AChR and L-AChR classes have been described, we explored the behavioral (by paralysis assays) and molecular actions (by patch clamp recordings) of the antiparasitic bephenium. As in parasites, bephenium produced spastic paralysis. A mutant strain lacking the L-AChR showed full resistance to bephenium, indicating that this receptor is the drug target. Bephenium activated L-AChRs from isolated larvae muscle cells, eliciting channel activity as that elicited by levamisole. The analysis revealed that it is a potent agonist of the L-AChR and an open-channel blocker at higher concentrations. In contrast, we demonstrated that it is a very low efficacious agonist of the mammalian muscle nAChR. Molecular docking studies proposed that bephenium can form key interactions required for activation in mammalian and nematode nAChRs, revealed differences with ACh binding, and provided explanations for the experimental results.Fil: Turani, Ornella. 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: 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; 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; Argentina6th International Iberian Biophysics Congress and X Iberoamerican Congress of BiophysicsCastellonEspañaSociedad de Biofísica de EspañaSociedad de Biofísica de EspañaSalgado, JesúsAlegre Cebollada, JorgeDaura, XavierGiráldez, Teresa2018info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/conferenceObjectCongresoJournalhttp://purl.org/coar/resource_type/c_5794info:ar-repo/semantics/documentoDeConferenciaapplication/pdfapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/231622The antiparasitic bephenium is a potent agonist of Caenorhabditis elegans levamisole-sensitive nicotinic receptors; 6th International Iberian Biophysics Congress and X Iberoamerican Congress of Biophysics; Castellon; España; 2018; 124-1242445-43111CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/http://biofisica.info/6th-iberian-10th-iberoamerican-biophysics-congress/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 Técnicas2025-09-03T09:57:47Zoai:ri.conicet.gov.ar:11336/231622instacron: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 09:57:48.212CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse |
dc.title.none.fl_str_mv |
The antiparasitic bephenium is a potent agonist of Caenorhabditis elegans levamisole-sensitive nicotinic receptors |
title |
The antiparasitic bephenium is a potent agonist of Caenorhabditis elegans levamisole-sensitive nicotinic receptors |
spellingShingle |
The antiparasitic bephenium is a potent agonist of Caenorhabditis elegans levamisole-sensitive nicotinic receptors Turani, Ornella CAENORHABDITIS ELEGANS CYS-LOOP RECEPTORS BEPHENIUM ANTHELMINTICS |
title_short |
The antiparasitic bephenium is a potent agonist of Caenorhabditis elegans levamisole-sensitive nicotinic receptors |
title_full |
The antiparasitic bephenium is a potent agonist of Caenorhabditis elegans levamisole-sensitive nicotinic receptors |
title_fullStr |
The antiparasitic bephenium is a potent agonist of Caenorhabditis elegans levamisole-sensitive nicotinic receptors |
title_full_unstemmed |
The antiparasitic bephenium is a potent agonist of Caenorhabditis elegans levamisole-sensitive nicotinic receptors |
title_sort |
The antiparasitic bephenium is a potent agonist of Caenorhabditis elegans levamisole-sensitive nicotinic receptors |
dc.creator.none.fl_str_mv |
Turani, Ornella Hernando, Guillermina Silvana Corradi, Jeremias Bouzat, Cecilia Beatriz |
author |
Turani, Ornella |
author_facet |
Turani, Ornella 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 |
Salgado, Jesús Alegre Cebollada, Jorge Daura, Xavier Giráldez, Teresa |
dc.subject.none.fl_str_mv |
CAENORHABDITIS ELEGANS CYS-LOOP RECEPTORS BEPHENIUM ANTHELMINTICS |
topic |
CAENORHABDITIS ELEGANS CYS-LOOP RECEPTORS BEPHENIUM ANTHELMINTICS |
purl_subject.fl_str_mv |
https://purl.org/becyt/ford/1.6 https://purl.org/becyt/ford/1 |
dc.description.none.fl_txt_mv |
Nicotinic acetylcholine receptors (nAChRs) are ligand-gated ion channels involved in neuromuscular transmission. In nematodes, muscle nAChRs are main targets of antiparasitic drugs. Nematode parasites contain three pharmacological classes of muscle nAChRs, which are activated by levamisole (L-type), nicotine (N-type) and bephenium (B-type). The free-living nematode Caenorhabditis elegans is a model of parasitic nematodes, useful for drug discovery. Because in C. elegans muscle only the N-AChR and L-AChR classes have been described, we explored the behavioral (by paralysis assays) and molecular actions (by patch clamp recordings) of the antiparasitic bephenium. As in parasites, bephenium produced spastic paralysis. A mutant strain lacking the L-AChR showed full resistance to bephenium, indicating that this receptor is the drug target. Bephenium activated L-AChRs from isolated larvae muscle cells, eliciting channel activity as that elicited by levamisole. The analysis revealed that it is a potent agonist of the L-AChR and an open-channel blocker at higher concentrations. In contrast, we demonstrated that it is a very low efficacious agonist of the mammalian muscle nAChR. Molecular docking studies proposed that bephenium can form key interactions required for activation in mammalian and nematode nAChRs, revealed differences with ACh binding, and provided explanations for the experimental results. Fil: Turani, Ornella. 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: 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 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 6th International Iberian Biophysics Congress and X Iberoamerican Congress of Biophysics Castellon España Sociedad de Biofísica de España |
description |
Nicotinic acetylcholine receptors (nAChRs) are ligand-gated ion channels involved in neuromuscular transmission. In nematodes, muscle nAChRs are main targets of antiparasitic drugs. Nematode parasites contain three pharmacological classes of muscle nAChRs, which are activated by levamisole (L-type), nicotine (N-type) and bephenium (B-type). The free-living nematode Caenorhabditis elegans is a model of parasitic nematodes, useful for drug discovery. Because in C. elegans muscle only the N-AChR and L-AChR classes have been described, we explored the behavioral (by paralysis assays) and molecular actions (by patch clamp recordings) of the antiparasitic bephenium. As in parasites, bephenium produced spastic paralysis. A mutant strain lacking the L-AChR showed full resistance to bephenium, indicating that this receptor is the drug target. Bephenium activated L-AChRs from isolated larvae muscle cells, eliciting channel activity as that elicited by levamisole. The analysis revealed that it is a potent agonist of the L-AChR and an open-channel blocker at higher concentrations. In contrast, we demonstrated that it is a very low efficacious agonist of the mammalian muscle nAChR. Molecular docking studies proposed that bephenium can form key interactions required for activation in mammalian and nematode nAChRs, revealed differences with ACh binding, and provided explanations for the experimental results. |
publishDate |
2018 |
dc.date.none.fl_str_mv |
2018 |
dc.type.none.fl_str_mv |
info:eu-repo/semantics/publishedVersion info:eu-repo/semantics/conferenceObject Congreso 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/11336/231622 The antiparasitic bephenium is a potent agonist of Caenorhabditis elegans levamisole-sensitive nicotinic receptors; 6th International Iberian Biophysics Congress and X Iberoamerican Congress of Biophysics; Castellon; España; 2018; 124-124 2445-43111 CONICET Digital CONICET |
url |
http://hdl.handle.net/11336/231622 |
identifier_str_mv |
The antiparasitic bephenium is a potent agonist of Caenorhabditis elegans levamisole-sensitive nicotinic receptors; 6th International Iberian Biophysics Congress and X Iberoamerican Congress of Biophysics; Castellon; España; 2018; 124-124 2445-43111 CONICET Digital CONICET |
dc.language.none.fl_str_mv |
eng |
language |
eng |
dc.relation.none.fl_str_mv |
info:eu-repo/semantics/altIdentifier/url/http://biofisica.info/6th-iberian-10th-iberoamerican-biophysics-congress/ |
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 application/pdf |
dc.coverage.none.fl_str_mv |
Internacional |
dc.publisher.none.fl_str_mv |
Sociedad de Biofísica de España |
publisher.none.fl_str_mv |
Sociedad de Biofísica de España |
dc.source.none.fl_str_mv |
reponame:CONICET Digital (CONICET) instname:Consejo Nacional de Investigaciones Científicas y Técnicas |
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CONICET Digital (CONICET) |
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CONICET Digital (CONICET) |
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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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1842269484906184704 |
score |
13.13397 |