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
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/231622
Acceder
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network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling 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 Técnicas2025-09-29T10:04:28Zoai: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:34982025-09-29 10:04:29.182CONICET 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
reponame_str CONICET Digital (CONICET)
collection CONICET Digital (CONICET)
instname_str 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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