Activation of Caenorhabditis elegans Levamisole-Sensitive and Mammalian Nicotinic Receptors by the Antiparasitic Bephenium

Autores
Turani, Ornella; Hernando, Guillermina Silvana; Corradi, Jeremias; Bouzat, Cecilia Beatriz
Año de publicación
2018
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Nicotinic acetylcholine receptors (nAChRs) are ligand-gated ion channels involved in neuromuscular transmission. In nematodes, muscle nAChRs are targets of antiparasitic drugs. Bephenium is an anthelmintic compound whose molecular action in the free-living nematode Caenorhabditis elegans, which is a model for anthelmintic drug discovery, is poorly known. We explored the effect of bephenium on C. Elegans locomotion and applied single-channel recordings to identify its molecular target, mechanism of action, and selectivity between mammalian and C. Elegans nAChRs. As in parasites, bephenium paralyzes C. Elegans. A mutant strain lacking the muscle levamisolesensitive nAChR (L-AChR) shows full resistance to bephenium, indicating that this receptor is the target site. Bephenium activates L-AChR channels from larvae muscle cells in the micromolar range. Channel activity is similar to that elicited by levamisole, appearing mainly as isolated brief openings. Our analysis revealed that bephenium is an agonist of L-AChR and an open-channel blocker at higher concentrations. It also activates mammalian muscle nAChRs. Opening events are significantly briefer than those elicited by ACh and do not appear in activation episodes at a range of concentrations, indicating that it is a very weak agonist of mammalian nAChRs. Recordings in the presence of ACh showed that bephenium acts as a voltagedependent channel blocker and a low-affinity agonist. Molecular docking into homology-modeled binding-site interfaces represent the binding mode of bephenium that explains its partial agonism. Given the great diversity of helminth nAChRs and the overlap of their pharmacological profiles, unraveling the basis of drug receptor-selectivity will be required for rational design of anthelmintic drugs.
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. 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
Materia
NICOTINIC ACETYLCHOLINE RECEPTORS
BEPHENIUM
CAENORHABDITIS ELEGANS
ANTIPARASITIC DRUGS
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:11336/85523
Acceder
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repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Activation of Caenorhabditis elegans Levamisole-Sensitive and Mammalian Nicotinic Receptors by the Antiparasitic BepheniumTurani, OrnellaHernando, Guillermina SilvanaCorradi, JeremiasBouzat, Cecilia BeatrizNICOTINIC ACETYLCHOLINE RECEPTORSBEPHENIUMCAENORHABDITIS ELEGANSANTIPARASITIC DRUGShttps://purl.org/becyt/ford/3.1https://purl.org/becyt/ford/3Nicotinic acetylcholine receptors (nAChRs) are ligand-gated ion channels involved in neuromuscular transmission. In nematodes, muscle nAChRs are targets of antiparasitic drugs. Bephenium is an anthelmintic compound whose molecular action in the free-living nematode Caenorhabditis elegans, which is a model for anthelmintic drug discovery, is poorly known. We explored the effect of bephenium on C. Elegans locomotion and applied single-channel recordings to identify its molecular target, mechanism of action, and selectivity between mammalian and C. Elegans nAChRs. As in parasites, bephenium paralyzes C. Elegans. A mutant strain lacking the muscle levamisolesensitive nAChR (L-AChR) shows full resistance to bephenium, indicating that this receptor is the target site. Bephenium activates L-AChR channels from larvae muscle cells in the micromolar range. Channel activity is similar to that elicited by levamisole, appearing mainly as isolated brief openings. Our analysis revealed that bephenium is an agonist of L-AChR and an open-channel blocker at higher concentrations. It also activates mammalian muscle nAChRs. Opening events are significantly briefer than those elicited by ACh and do not appear in activation episodes at a range of concentrations, indicating that it is a very weak agonist of mammalian nAChRs. Recordings in the presence of ACh showed that bephenium acts as a voltagedependent channel blocker and a low-affinity agonist. Molecular docking into homology-modeled binding-site interfaces represent the binding mode of bephenium that explains its partial agonism. Given the great diversity of helminth nAChRs and the overlap of their pharmacological profiles, unraveling the basis of drug receptor-selectivity will be required for rational design of anthelmintic drugs.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; 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; ArgentinaAmerican Society for Pharmacology and Experimental Therapeutics2018-11info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/85523Turani, Ornella; Hernando, Guillermina Silvana; Corradi, Jeremias; Bouzat, Cecilia Beatriz; Activation of Caenorhabditis elegans Levamisole-Sensitive and Mammalian Nicotinic Receptors by the Antiparasitic Bephenium; American Society for Pharmacology and Experimental Therapeutics; Molecular Pharmacology; 94; 5; 11-2018; 1270-12790026-895XCONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/http://molpharm.aspetjournals.org/lookup/doi/10.1124/mol.118.113357info:eu-repo/semantics/altIdentifier/doi/10.1124/mol.118.113357info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-03T10:02:16Zoai:ri.conicet.gov.ar:11336/85523instacron: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 10:02:17.039CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Activation of Caenorhabditis elegans Levamisole-Sensitive and Mammalian Nicotinic Receptors by the Antiparasitic Bephenium
title Activation of Caenorhabditis elegans Levamisole-Sensitive and Mammalian Nicotinic Receptors by the Antiparasitic Bephenium
spellingShingle Activation of Caenorhabditis elegans Levamisole-Sensitive and Mammalian Nicotinic Receptors by the Antiparasitic Bephenium
Turani, Ornella
NICOTINIC ACETYLCHOLINE RECEPTORS
BEPHENIUM
CAENORHABDITIS ELEGANS
ANTIPARASITIC DRUGS
title_short Activation of Caenorhabditis elegans Levamisole-Sensitive and Mammalian Nicotinic Receptors by the Antiparasitic Bephenium
title_full Activation of Caenorhabditis elegans Levamisole-Sensitive and Mammalian Nicotinic Receptors by the Antiparasitic Bephenium
title_fullStr Activation of Caenorhabditis elegans Levamisole-Sensitive and Mammalian Nicotinic Receptors by the Antiparasitic Bephenium
title_full_unstemmed Activation of Caenorhabditis elegans Levamisole-Sensitive and Mammalian Nicotinic Receptors by the Antiparasitic Bephenium
title_sort Activation of Caenorhabditis elegans Levamisole-Sensitive and Mammalian Nicotinic Receptors by the Antiparasitic Bephenium
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.subject.none.fl_str_mv NICOTINIC ACETYLCHOLINE RECEPTORS
BEPHENIUM
CAENORHABDITIS ELEGANS
ANTIPARASITIC DRUGS
topic NICOTINIC ACETYLCHOLINE RECEPTORS
BEPHENIUM
CAENORHABDITIS ELEGANS
ANTIPARASITIC DRUGS
purl_subject.fl_str_mv https://purl.org/becyt/ford/3.1
https://purl.org/becyt/ford/3
dc.description.none.fl_txt_mv Nicotinic acetylcholine receptors (nAChRs) are ligand-gated ion channels involved in neuromuscular transmission. In nematodes, muscle nAChRs are targets of antiparasitic drugs. Bephenium is an anthelmintic compound whose molecular action in the free-living nematode Caenorhabditis elegans, which is a model for anthelmintic drug discovery, is poorly known. We explored the effect of bephenium on C. Elegans locomotion and applied single-channel recordings to identify its molecular target, mechanism of action, and selectivity between mammalian and C. Elegans nAChRs. As in parasites, bephenium paralyzes C. Elegans. A mutant strain lacking the muscle levamisolesensitive nAChR (L-AChR) shows full resistance to bephenium, indicating that this receptor is the target site. Bephenium activates L-AChR channels from larvae muscle cells in the micromolar range. Channel activity is similar to that elicited by levamisole, appearing mainly as isolated brief openings. Our analysis revealed that bephenium is an agonist of L-AChR and an open-channel blocker at higher concentrations. It also activates mammalian muscle nAChRs. Opening events are significantly briefer than those elicited by ACh and do not appear in activation episodes at a range of concentrations, indicating that it is a very weak agonist of mammalian nAChRs. Recordings in the presence of ACh showed that bephenium acts as a voltagedependent channel blocker and a low-affinity agonist. Molecular docking into homology-modeled binding-site interfaces represent the binding mode of bephenium that explains its partial agonism. Given the great diversity of helminth nAChRs and the overlap of their pharmacological profiles, unraveling the basis of drug receptor-selectivity will be required for rational design of anthelmintic drugs.
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. 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
description Nicotinic acetylcholine receptors (nAChRs) are ligand-gated ion channels involved in neuromuscular transmission. In nematodes, muscle nAChRs are targets of antiparasitic drugs. Bephenium is an anthelmintic compound whose molecular action in the free-living nematode Caenorhabditis elegans, which is a model for anthelmintic drug discovery, is poorly known. We explored the effect of bephenium on C. Elegans locomotion and applied single-channel recordings to identify its molecular target, mechanism of action, and selectivity between mammalian and C. Elegans nAChRs. As in parasites, bephenium paralyzes C. Elegans. A mutant strain lacking the muscle levamisolesensitive nAChR (L-AChR) shows full resistance to bephenium, indicating that this receptor is the target site. Bephenium activates L-AChR channels from larvae muscle cells in the micromolar range. Channel activity is similar to that elicited by levamisole, appearing mainly as isolated brief openings. Our analysis revealed that bephenium is an agonist of L-AChR and an open-channel blocker at higher concentrations. It also activates mammalian muscle nAChRs. Opening events are significantly briefer than those elicited by ACh and do not appear in activation episodes at a range of concentrations, indicating that it is a very weak agonist of mammalian nAChRs. Recordings in the presence of ACh showed that bephenium acts as a voltagedependent channel blocker and a low-affinity agonist. Molecular docking into homology-modeled binding-site interfaces represent the binding mode of bephenium that explains its partial agonism. Given the great diversity of helminth nAChRs and the overlap of their pharmacological profiles, unraveling the basis of drug receptor-selectivity will be required for rational design of anthelmintic drugs.
publishDate 2018
dc.date.none.fl_str_mv 2018-11
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/85523
Turani, Ornella; Hernando, Guillermina Silvana; Corradi, Jeremias; Bouzat, Cecilia Beatriz; Activation of Caenorhabditis elegans Levamisole-Sensitive and Mammalian Nicotinic Receptors by the Antiparasitic Bephenium; American Society for Pharmacology and Experimental Therapeutics; Molecular Pharmacology; 94; 5; 11-2018; 1270-1279
0026-895X
CONICET Digital
CONICET
url http://hdl.handle.net/11336/85523
identifier_str_mv Turani, Ornella; Hernando, Guillermina Silvana; Corradi, Jeremias; Bouzat, Cecilia Beatriz; Activation of Caenorhabditis elegans Levamisole-Sensitive and Mammalian Nicotinic Receptors by the Antiparasitic Bephenium; American Society for Pharmacology and Experimental Therapeutics; Molecular Pharmacology; 94; 5; 11-2018; 1270-1279
0026-895X
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://molpharm.aspetjournals.org/lookup/doi/10.1124/mol.118.113357
info:eu-repo/semantics/altIdentifier/doi/10.1124/mol.118.113357
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.publisher.none.fl_str_mv American Society for Pharmacology and Experimental Therapeutics
publisher.none.fl_str_mv American Society for Pharmacology and Experimental Therapeutics
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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