MOD-1 receptor as a novel drug target for anthelmintic therapy

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
Caenorhabditis elegans (Nematoda) contains a homomeric 5HT-gated chloride channel, MOD-1, that belongs to the Cys-loop receptor family and modulates locomotor behavior. Although it binds 5-HT, MOD-1 is not present in vertebrates, and it therefore emerges as a possible anthelmintic target. We deciphered MOD-1 pharma- cological properties and searched for novel modulators with poten- tial anthelmintic activity by performing patch-clamp recordings from mammalian cells heterologously expressing MOD-1 and locomotor activity assays in C. elegans. Whole-cell recordings showed that MOD-1 desensitizes slowly and recovers from desensitization with a time constant of about 1 s. Compared to the vertebrate 5-HT3 A receptor, dose-response curves were similar for 5-HT but very differ- ent for the orthosteric agonists tryptamine and 2-Me-5HT. The an- thelmintic drugs ivermectin (IVM), levamisole, and piperazine (PZE), which are agonists of other Cys-loop receptors, did not activate MOD-1. However, IVM produced a slight and irreversible inhibition and PZE produced a profound and reversible inhibition of MOD-1 currents elicited by 5-HT. The analysis indicated that PZE is a non- competitive antagonist of MOD-1, revealing a novel function of this drug. To relate the molecular effects to behavioral actions of these compounds, we performed locomotor activity assays in C. elegans. We found that 5-HT produces rapid and reversible paralysis of wild- type (WT) worms while MOD-1 mutants are partially resistant under similar conditions, thus indicating that MOD-1 is the main 5-HT tar- get in this type of assays. Additional assays using drug combinations in WT and mutant strains confirmed the inhibition of MOD-1 activity by IVM and PZE. The elucidation of the molecular pharmacology of MOD-1 enhances our knowledge of function and drug selectivity of Cys-loop receptors and contributes to determine 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. 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
LXVI Reunión Anual de la Sociedad Argentina de Investigación Clínica; LXIX Reunión Anual de la Sociedad Argentina de Inmunología; LIII Reunión Anual de la Asociación Argentina de Farmacología Experimental y XI Reunión Anual De La Asociación Argentina De Nanomedicinas
Buenos Aires
Argentina
Sociedad Argentina de Investigación Clínica
Sociedad Argentina de Inmunología
Asociación Argentina de Farmacología Experimental
Asociación Argentina de Nanomedicinas
Materia
RECEPTORES CYS-LOOP
MOD-1
C. ELEGANS
PIPERAZINE
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:11336/184967
Acceder
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network_name_str CONICET Digital (CONICET)
spelling MOD-1 receptor as a novel drug target for anthelmintic therapyRodriguez Araujo, NoeliaHernando, Guillermina SilvanaCorradi, JeremiasBouzat, Cecilia BeatrizRECEPTORES CYS-LOOPMOD-1C. ELEGANSPIPERAZINEhttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1Caenorhabditis elegans (Nematoda) contains a homomeric 5HT-gated chloride channel, MOD-1, that belongs to the Cys-loop receptor family and modulates locomotor behavior. Although it binds 5-HT, MOD-1 is not present in vertebrates, and it therefore emerges as a possible anthelmintic target. We deciphered MOD-1 pharma- cological properties and searched for novel modulators with poten- tial anthelmintic activity by performing patch-clamp recordings from mammalian cells heterologously expressing MOD-1 and locomotor activity assays in C. elegans. Whole-cell recordings showed that MOD-1 desensitizes slowly and recovers from desensitization with a time constant of about 1 s. Compared to the vertebrate 5-HT3 A receptor, dose-response curves were similar for 5-HT but very differ- ent for the orthosteric agonists tryptamine and 2-Me-5HT. The an- thelmintic drugs ivermectin (IVM), levamisole, and piperazine (PZE), which are agonists of other Cys-loop receptors, did not activate MOD-1. However, IVM produced a slight and irreversible inhibition and PZE produced a profound and reversible inhibition of MOD-1 currents elicited by 5-HT. The analysis indicated that PZE is a non- competitive antagonist of MOD-1, revealing a novel function of this drug. To relate the molecular effects to behavioral actions of these compounds, we performed locomotor activity assays in C. elegans. We found that 5-HT produces rapid and reversible paralysis of wild- type (WT) worms while MOD-1 mutants are partially resistant under similar conditions, thus indicating that MOD-1 is the main 5-HT tar- get in this type of assays. Additional assays using drug combinations in WT and mutant strains confirmed the inhibition of MOD-1 activity by IVM and PZE. The elucidation of the molecular pharmacology of MOD-1 enhances our knowledge of function and drug selectivity of Cys-loop receptors and contributes to determine 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. 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; ArgentinaLXVI Reunión Anual de la Sociedad Argentina de Investigación Clínica; LXIX Reunión Anual de la Sociedad Argentina de Inmunología; LIII Reunión Anual de la Asociación Argentina de Farmacología Experimental y XI Reunión Anual De La Asociación Argentina De NanomedicinasBuenos AiresArgentinaSociedad Argentina de Investigación ClínicaSociedad Argentina de InmunologíaAsociación Argentina de Farmacología ExperimentalAsociación Argentina de NanomedicinasFundación Revista Medicina2021info: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/11336/184967MOD-1 receptor as a novel drug target for anthelmintic therapy; LXVI Reunión Anual de la Sociedad Argentina de Investigación Clínica; LXIX Reunión Anual de la Sociedad Argentina de Inmunología; LIII Reunión Anual de la Asociación Argentina de Farmacología Experimental y XI Reunión Anual De La Asociación Argentina De Nanomedicinas; Buenos Aires; Argentina; 2021; 97-971669-9106CONICET 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 Técnicas2025-09-29T10:26:56Zoai:ri.conicet.gov.ar:11336/184967instacron: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 10:26:56.927CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv MOD-1 receptor as a novel drug target for anthelmintic therapy
title MOD-1 receptor as a novel drug target for anthelmintic therapy
spellingShingle MOD-1 receptor as a novel drug target for anthelmintic therapy
Rodriguez Araujo, Noelia
RECEPTORES CYS-LOOP
MOD-1
C. ELEGANS
PIPERAZINE
title_short MOD-1 receptor as a novel drug target for anthelmintic therapy
title_full MOD-1 receptor as a novel drug target for anthelmintic therapy
title_fullStr MOD-1 receptor as a novel drug target for anthelmintic therapy
title_full_unstemmed MOD-1 receptor as a novel drug target for anthelmintic therapy
title_sort MOD-1 receptor as a novel drug target for anthelmintic therapy
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.subject.none.fl_str_mv RECEPTORES CYS-LOOP
MOD-1
C. ELEGANS
PIPERAZINE
topic RECEPTORES CYS-LOOP
MOD-1
C. ELEGANS
PIPERAZINE
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.6
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv Caenorhabditis elegans (Nematoda) contains a homomeric 5HT-gated chloride channel, MOD-1, that belongs to the Cys-loop receptor family and modulates locomotor behavior. Although it binds 5-HT, MOD-1 is not present in vertebrates, and it therefore emerges as a possible anthelmintic target. We deciphered MOD-1 pharma- cological properties and searched for novel modulators with poten- tial anthelmintic activity by performing patch-clamp recordings from mammalian cells heterologously expressing MOD-1 and locomotor activity assays in C. elegans. Whole-cell recordings showed that MOD-1 desensitizes slowly and recovers from desensitization with a time constant of about 1 s. Compared to the vertebrate 5-HT3 A receptor, dose-response curves were similar for 5-HT but very differ- ent for the orthosteric agonists tryptamine and 2-Me-5HT. The an- thelmintic drugs ivermectin (IVM), levamisole, and piperazine (PZE), which are agonists of other Cys-loop receptors, did not activate MOD-1. However, IVM produced a slight and irreversible inhibition and PZE produced a profound and reversible inhibition of MOD-1 currents elicited by 5-HT. The analysis indicated that PZE is a non- competitive antagonist of MOD-1, revealing a novel function of this drug. To relate the molecular effects to behavioral actions of these compounds, we performed locomotor activity assays in C. elegans. We found that 5-HT produces rapid and reversible paralysis of wild- type (WT) worms while MOD-1 mutants are partially resistant under similar conditions, thus indicating that MOD-1 is the main 5-HT tar- get in this type of assays. Additional assays using drug combinations in WT and mutant strains confirmed the inhibition of MOD-1 activity by IVM and PZE. The elucidation of the molecular pharmacology of MOD-1 enhances our knowledge of function and drug selectivity of Cys-loop receptors and contributes to determine 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. 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
LXVI Reunión Anual de la Sociedad Argentina de Investigación Clínica; LXIX Reunión Anual de la Sociedad Argentina de Inmunología; LIII Reunión Anual de la Asociación Argentina de Farmacología Experimental y XI Reunión Anual De La Asociación Argentina De Nanomedicinas
Buenos Aires
Argentina
Sociedad Argentina de Investigación Clínica
Sociedad Argentina de Inmunología
Asociación Argentina de Farmacología Experimental
Asociación Argentina de Nanomedicinas
description Caenorhabditis elegans (Nematoda) contains a homomeric 5HT-gated chloride channel, MOD-1, that belongs to the Cys-loop receptor family and modulates locomotor behavior. Although it binds 5-HT, MOD-1 is not present in vertebrates, and it therefore emerges as a possible anthelmintic target. We deciphered MOD-1 pharma- cological properties and searched for novel modulators with poten- tial anthelmintic activity by performing patch-clamp recordings from mammalian cells heterologously expressing MOD-1 and locomotor activity assays in C. elegans. Whole-cell recordings showed that MOD-1 desensitizes slowly and recovers from desensitization with a time constant of about 1 s. Compared to the vertebrate 5-HT3 A receptor, dose-response curves were similar for 5-HT but very differ- ent for the orthosteric agonists tryptamine and 2-Me-5HT. The an- thelmintic drugs ivermectin (IVM), levamisole, and piperazine (PZE), which are agonists of other Cys-loop receptors, did not activate MOD-1. However, IVM produced a slight and irreversible inhibition and PZE produced a profound and reversible inhibition of MOD-1 currents elicited by 5-HT. The analysis indicated that PZE is a non- competitive antagonist of MOD-1, revealing a novel function of this drug. To relate the molecular effects to behavioral actions of these compounds, we performed locomotor activity assays in C. elegans. We found that 5-HT produces rapid and reversible paralysis of wild- type (WT) worms while MOD-1 mutants are partially resistant under similar conditions, thus indicating that MOD-1 is the main 5-HT tar- get in this type of assays. Additional assays using drug combinations in WT and mutant strains confirmed the inhibition of MOD-1 activity by IVM and PZE. The elucidation of the molecular pharmacology of MOD-1 enhances our knowledge of function and drug selectivity of Cys-loop receptors and contributes to determine its potential as a novel target for anthelmintic therapy.
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
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/11336/184967
MOD-1 receptor as a novel drug target for anthelmintic therapy; LXVI Reunión Anual de la Sociedad Argentina de Investigación Clínica; LXIX Reunión Anual de la Sociedad Argentina de Inmunología; LIII Reunión Anual de la Asociación Argentina de Farmacología Experimental y XI Reunión Anual De La Asociación Argentina De Nanomedicinas; Buenos Aires; Argentina; 2021; 97-97
1669-9106
CONICET Digital
CONICET
url http://hdl.handle.net/11336/184967
identifier_str_mv MOD-1 receptor as a novel drug target for anthelmintic therapy; LXVI Reunión Anual de la Sociedad Argentina de Investigación Clínica; LXIX Reunión Anual de la Sociedad Argentina de Inmunología; LIII Reunión Anual de la Asociación Argentina de Farmacología Experimental y XI Reunión Anual De La Asociación Argentina De Nanomedicinas; Buenos Aires; Argentina; 2021; 97-97
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
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/
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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
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repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
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