A new antagonist of caenorhabditis elegans glutamate-activated chloride channels with anthelmintic activity
- Autores
- Castro, Maria Julia; Turani, Ornella; Faraoni, María Belén; Gerbino, Darío César; Bouzat, Cecilia Beatriz
- Año de publicación
- 2020
- Idioma
- inglés
- Tipo de recurso
- artículo
- Estado
- versión publicada
- Descripción
- Nematode parasitosis causes significant mortality and morbidity in humans andconsiderable losses in livestock and domestic animals. The acquisition of resistanceto current anthelmintic drugs has prompted the search for new compounds for whichthe free-living nematode Caenorhabditis elegans has emerged as a valuable platform.We have previously synthetized a small library of oxygenated tricyclic compoundsand determined that dibenzo[b,e]oxepin-11(6H)-one (doxepinone) inhibits C. elegansmotility. Because doxepinone shows potential anthelmintic activity, we explored itsbehavioral effects and deciphered its target site and mechanism of action on C. elegans.Doxepinone reduces swimming rate, induces paralysis, and decreases the rate ofpharyngeal pumping required for feeding, indicating a marked anthelmintic activity. Toidentify the main drug targets, we performed an in vivo screening of selected strainscarrying mutations in Cys-loop receptors involved in worm locomotion for determiningresistance to doxepinone effects. A mutant strain that lacks subunit genes of theinvertebrate glutamate-gated chloride channels (GluCl), which are targets of the widelyused antiparasitic ivermectin (IVM), is resistant to doxepinone effects. To unravel themolecular mechanism, we measured whole-cell currents from GluCla1/b receptorsexpressed in mammalian cells. Glutamate elicits macroscopic currents whereas noresponses are elicited by doxepinone, indicating that it is not an agonist of GluCls.Preincubation of the cell with doxepinone produces a statistically significant decrease ofthe decay time constant and net charge of glutamate-elicited currents, indicating that itinhibits GluCls, which contrasts to IVM molecular actions. Thus, we identify doxepinoneas an attractive scaffold with promising anthelmintic activity and propose the inhibitionof GluCls as a potential anthelmintic mechanism of action.
Fil: Castro, Maria Julia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Química del Sur. Universidad Nacional del Sur. Departamento de Química. Instituto de Química del Sur; Argentina. 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: 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: Faraoni, María Belén. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Química del Sur. Universidad Nacional del Sur. Departamento de Química. Instituto de Química del Sur; Argentina
Fil: Gerbino, Darío César. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Química del Sur. Universidad Nacional del Sur. Departamento de Química. Instituto de Química del Sur; Argentina
Fil: Bouzat, Cecilia Beatriz. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Ciencias Biológicas y Biomédicas del Sur. Universidad Nacional del Sur. Departamento de Biología, Bioquímica y Farmacia. Instituto de Ciencias Biológicas y Biomédicas del Sur; Argentina - Materia
-
C. ELEGANS
CYS-LOOP RECEPTORS
GLUTAMATE-ACTIVATED-CHLORIDE CHANNELS
PATCH-CLAMP - 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:11336/142042
Ver los metadatos del registro completo
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A new antagonist of caenorhabditis elegans glutamate-activated chloride channels with anthelmintic activityCastro, Maria JuliaTurani, OrnellaFaraoni, María BelénGerbino, Darío CésarBouzat, Cecilia BeatrizC. ELEGANSCYS-LOOP RECEPTORSGLUTAMATE-ACTIVATED-CHLORIDE CHANNELSPATCH-CLAMPhttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1Nematode parasitosis causes significant mortality and morbidity in humans andconsiderable losses in livestock and domestic animals. The acquisition of resistanceto current anthelmintic drugs has prompted the search for new compounds for whichthe free-living nematode Caenorhabditis elegans has emerged as a valuable platform.We have previously synthetized a small library of oxygenated tricyclic compoundsand determined that dibenzo[b,e]oxepin-11(6H)-one (doxepinone) inhibits C. elegansmotility. Because doxepinone shows potential anthelmintic activity, we explored itsbehavioral effects and deciphered its target site and mechanism of action on C. elegans.Doxepinone reduces swimming rate, induces paralysis, and decreases the rate ofpharyngeal pumping required for feeding, indicating a marked anthelmintic activity. Toidentify the main drug targets, we performed an in vivo screening of selected strainscarrying mutations in Cys-loop receptors involved in worm locomotion for determiningresistance to doxepinone effects. A mutant strain that lacks subunit genes of theinvertebrate glutamate-gated chloride channels (GluCl), which are targets of the widelyused antiparasitic ivermectin (IVM), is resistant to doxepinone effects. To unravel themolecular mechanism, we measured whole-cell currents from GluCla1/b receptorsexpressed in mammalian cells. Glutamate elicits macroscopic currents whereas noresponses are elicited by doxepinone, indicating that it is not an agonist of GluCls.Preincubation of the cell with doxepinone produces a statistically significant decrease ofthe decay time constant and net charge of glutamate-elicited currents, indicating that itinhibits GluCls, which contrasts to IVM molecular actions. Thus, we identify doxepinoneas an attractive scaffold with promising anthelmintic activity and propose the inhibitionof GluCls as a potential anthelmintic mechanism of action.Fil: Castro, Maria Julia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Química del Sur. Universidad Nacional del Sur. Departamento de Química. Instituto de Química del Sur; Argentina. 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: 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: Faraoni, María Belén. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Química del Sur. Universidad Nacional del Sur. Departamento de Química. Instituto de Química del Sur; ArgentinaFil: Gerbino, Darío César. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Química del Sur. Universidad Nacional del Sur. Departamento de Química. Instituto de Química del Sur; ArgentinaFil: Bouzat, Cecilia Beatriz. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Ciencias Biológicas y Biomédicas del Sur. Universidad Nacional del Sur. Departamento de Biología, Bioquímica y Farmacia. Instituto de Ciencias Biológicas y Biomédicas del Sur; ArgentinaFrontiers Media2020-08-19info: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/11336/142042Castro, Maria Julia; Turani, Ornella; Faraoni, María Belén; Gerbino, Darío César; Bouzat, Cecilia Beatriz; A new antagonist of caenorhabditis elegans glutamate-activated chloride channels with anthelmintic activity; Frontiers Media; Frontiers in Neuroscience; 14; 19-8-2020; 1-121662-45481662-453XCONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7466757/info:eu-repo/semantics/altIdentifier/doi/10.3389/fnins.2020.00879info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-29T09:34:33Zoai:ri.conicet.gov.ar:11336/142042instacron: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 09:34:34.11CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse |
dc.title.none.fl_str_mv |
A new antagonist of caenorhabditis elegans glutamate-activated chloride channels with anthelmintic activity |
title |
A new antagonist of caenorhabditis elegans glutamate-activated chloride channels with anthelmintic activity |
spellingShingle |
A new antagonist of caenorhabditis elegans glutamate-activated chloride channels with anthelmintic activity Castro, Maria Julia C. ELEGANS CYS-LOOP RECEPTORS GLUTAMATE-ACTIVATED-CHLORIDE CHANNELS PATCH-CLAMP |
title_short |
A new antagonist of caenorhabditis elegans glutamate-activated chloride channels with anthelmintic activity |
title_full |
A new antagonist of caenorhabditis elegans glutamate-activated chloride channels with anthelmintic activity |
title_fullStr |
A new antagonist of caenorhabditis elegans glutamate-activated chloride channels with anthelmintic activity |
title_full_unstemmed |
A new antagonist of caenorhabditis elegans glutamate-activated chloride channels with anthelmintic activity |
title_sort |
A new antagonist of caenorhabditis elegans glutamate-activated chloride channels with anthelmintic activity |
dc.creator.none.fl_str_mv |
Castro, Maria Julia Turani, Ornella Faraoni, María Belén Gerbino, Darío César Bouzat, Cecilia Beatriz |
author |
Castro, Maria Julia |
author_facet |
Castro, Maria Julia Turani, Ornella Faraoni, María Belén Gerbino, Darío César Bouzat, Cecilia Beatriz |
author_role |
author |
author2 |
Turani, Ornella Faraoni, María Belén Gerbino, Darío César Bouzat, Cecilia Beatriz |
author2_role |
author author author author |
dc.subject.none.fl_str_mv |
C. ELEGANS CYS-LOOP RECEPTORS GLUTAMATE-ACTIVATED-CHLORIDE CHANNELS PATCH-CLAMP |
topic |
C. ELEGANS CYS-LOOP RECEPTORS GLUTAMATE-ACTIVATED-CHLORIDE CHANNELS PATCH-CLAMP |
purl_subject.fl_str_mv |
https://purl.org/becyt/ford/1.6 https://purl.org/becyt/ford/1 |
dc.description.none.fl_txt_mv |
Nematode parasitosis causes significant mortality and morbidity in humans andconsiderable losses in livestock and domestic animals. The acquisition of resistanceto current anthelmintic drugs has prompted the search for new compounds for whichthe free-living nematode Caenorhabditis elegans has emerged as a valuable platform.We have previously synthetized a small library of oxygenated tricyclic compoundsand determined that dibenzo[b,e]oxepin-11(6H)-one (doxepinone) inhibits C. elegansmotility. Because doxepinone shows potential anthelmintic activity, we explored itsbehavioral effects and deciphered its target site and mechanism of action on C. elegans.Doxepinone reduces swimming rate, induces paralysis, and decreases the rate ofpharyngeal pumping required for feeding, indicating a marked anthelmintic activity. Toidentify the main drug targets, we performed an in vivo screening of selected strainscarrying mutations in Cys-loop receptors involved in worm locomotion for determiningresistance to doxepinone effects. A mutant strain that lacks subunit genes of theinvertebrate glutamate-gated chloride channels (GluCl), which are targets of the widelyused antiparasitic ivermectin (IVM), is resistant to doxepinone effects. To unravel themolecular mechanism, we measured whole-cell currents from GluCla1/b receptorsexpressed in mammalian cells. Glutamate elicits macroscopic currents whereas noresponses are elicited by doxepinone, indicating that it is not an agonist of GluCls.Preincubation of the cell with doxepinone produces a statistically significant decrease ofthe decay time constant and net charge of glutamate-elicited currents, indicating that itinhibits GluCls, which contrasts to IVM molecular actions. Thus, we identify doxepinoneas an attractive scaffold with promising anthelmintic activity and propose the inhibitionof GluCls as a potential anthelmintic mechanism of action. Fil: Castro, Maria Julia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Química del Sur. Universidad Nacional del Sur. Departamento de Química. Instituto de Química del Sur; Argentina. 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: 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: Faraoni, María Belén. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Química del Sur. Universidad Nacional del Sur. Departamento de Química. Instituto de Química del Sur; Argentina Fil: Gerbino, Darío César. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Química del Sur. Universidad Nacional del Sur. Departamento de Química. Instituto de Química del Sur; Argentina Fil: Bouzat, Cecilia Beatriz. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Ciencias Biológicas y Biomédicas del Sur. Universidad Nacional del Sur. Departamento de Biología, Bioquímica y Farmacia. Instituto de Ciencias Biológicas y Biomédicas del Sur; Argentina |
description |
Nematode parasitosis causes significant mortality and morbidity in humans andconsiderable losses in livestock and domestic animals. The acquisition of resistanceto current anthelmintic drugs has prompted the search for new compounds for whichthe free-living nematode Caenorhabditis elegans has emerged as a valuable platform.We have previously synthetized a small library of oxygenated tricyclic compoundsand determined that dibenzo[b,e]oxepin-11(6H)-one (doxepinone) inhibits C. elegansmotility. Because doxepinone shows potential anthelmintic activity, we explored itsbehavioral effects and deciphered its target site and mechanism of action on C. elegans.Doxepinone reduces swimming rate, induces paralysis, and decreases the rate ofpharyngeal pumping required for feeding, indicating a marked anthelmintic activity. Toidentify the main drug targets, we performed an in vivo screening of selected strainscarrying mutations in Cys-loop receptors involved in worm locomotion for determiningresistance to doxepinone effects. A mutant strain that lacks subunit genes of theinvertebrate glutamate-gated chloride channels (GluCl), which are targets of the widelyused antiparasitic ivermectin (IVM), is resistant to doxepinone effects. To unravel themolecular mechanism, we measured whole-cell currents from GluCla1/b receptorsexpressed in mammalian cells. Glutamate elicits macroscopic currents whereas noresponses are elicited by doxepinone, indicating that it is not an agonist of GluCls.Preincubation of the cell with doxepinone produces a statistically significant decrease ofthe decay time constant and net charge of glutamate-elicited currents, indicating that itinhibits GluCls, which contrasts to IVM molecular actions. Thus, we identify doxepinoneas an attractive scaffold with promising anthelmintic activity and propose the inhibitionof GluCls as a potential anthelmintic mechanism of action. |
publishDate |
2020 |
dc.date.none.fl_str_mv |
2020-08-19 |
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/11336/142042 Castro, Maria Julia; Turani, Ornella; Faraoni, María Belén; Gerbino, Darío César; Bouzat, Cecilia Beatriz; A new antagonist of caenorhabditis elegans glutamate-activated chloride channels with anthelmintic activity; Frontiers Media; Frontiers in Neuroscience; 14; 19-8-2020; 1-12 1662-4548 1662-453X CONICET Digital CONICET |
url |
http://hdl.handle.net/11336/142042 |
identifier_str_mv |
Castro, Maria Julia; Turani, Ornella; Faraoni, María Belén; Gerbino, Darío César; Bouzat, Cecilia Beatriz; A new antagonist of caenorhabditis elegans glutamate-activated chloride channels with anthelmintic activity; Frontiers Media; Frontiers in Neuroscience; 14; 19-8-2020; 1-12 1662-4548 1662-453X 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.ncbi.nlm.nih.gov/pmc/articles/PMC7466757/ info:eu-repo/semantics/altIdentifier/doi/10.3389/fnins.2020.00879 |
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 |
Frontiers Media |
publisher.none.fl_str_mv |
Frontiers Media |
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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1844613069618020352 |
score |
13.070432 |