Mimicking Human Myasthenic Syndromes in C. elegans: Evaluation of Function and Drug Modulation of Nicotinic Receptors

Autores
Bergé, Ignacio; Hernando, Guillermina Silvana; Andreocci, Emanuel; Roccamo, Ana Maria; Bouzat, Cecilia Beatriz
Año de publicación
2015
Idioma
inglés
Tipo de recurso
documento de conferencia
Estado
versión publicada
Descripción
In humans, gain-of-function mutations in the muscle nicotinic receptor (AChR) lead to slowchannel congenital myasthenic syndromes (SCCMS), characterized by slow decay of endplate currents, destabilization of the closed channel and prolonged activation episodes of AChR. Our goal is to use the free-living nematode C. elegans to generate models of these human syndromes. To this end, we first generated transgenic worms expressing mutant LAChRs at 9' position of the M2 segment, which has been shown to form the gate of the ion channel in vertebrates. Electrophysiological recordings of L-AChRs from muscle cells of these transgenic worms show an increase of 11- to 14-fold of the open-channel lifetime and decreased desensitization rate with respect to wild-type, as expected for a gain-offunction mutation. We found that quinidine sulfate, a long-lived open-channel blocker of the human AChR used for the treatment of SCCMS, also reduces the open duration of the mutant C. elegans L-AChR. These results show that it is possible to mimic in C. elegans the molecular and functional changes observed in human AChRs as well as their responses to therapeutic drugs. We next generated mutant strains with L-AChRs mimicking gain-offunction mutations that lead to severe slow-channel CMS to be used as models of these human neuromuscular disorders for drug screening and development of therapeutic strategies
Fil: Bergé, Ignacio. 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: Andreocci, Emanuel. 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: Roccamo, Ana Maria. 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
XXX Reunión Anual de la Sociedad Argentina de Investigación en Neurociencias
Mar del Plata
Argentina
Sociedad Argentina de Investigación en Neurociencias
Materia
SCMS
PATCH-CLAMP
C.-ELEGANS
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:11336/237764
Acceder
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oai_identifier_str oai:ri.conicet.gov.ar:11336/237764
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Mimicking Human Myasthenic Syndromes in C. elegans: Evaluation of Function and Drug Modulation of Nicotinic ReceptorsBergé, IgnacioHernando, Guillermina SilvanaAndreocci, EmanuelRoccamo, Ana MariaBouzat, Cecilia BeatrizSCMSPATCH-CLAMPC.-ELEGANShttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1In humans, gain-of-function mutations in the muscle nicotinic receptor (AChR) lead to slowchannel congenital myasthenic syndromes (SCCMS), characterized by slow decay of endplate currents, destabilization of the closed channel and prolonged activation episodes of AChR. Our goal is to use the free-living nematode C. elegans to generate models of these human syndromes. To this end, we first generated transgenic worms expressing mutant LAChRs at 9' position of the M2 segment, which has been shown to form the gate of the ion channel in vertebrates. Electrophysiological recordings of L-AChRs from muscle cells of these transgenic worms show an increase of 11- to 14-fold of the open-channel lifetime and decreased desensitization rate with respect to wild-type, as expected for a gain-offunction mutation. We found that quinidine sulfate, a long-lived open-channel blocker of the human AChR used for the treatment of SCCMS, also reduces the open duration of the mutant C. elegans L-AChR. These results show that it is possible to mimic in C. elegans the molecular and functional changes observed in human AChRs as well as their responses to therapeutic drugs. We next generated mutant strains with L-AChRs mimicking gain-offunction mutations that lead to severe slow-channel CMS to be used as models of these human neuromuscular disorders for drug screening and development of therapeutic strategiesFil: Bergé, Ignacio. 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: Andreocci, Emanuel. 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: Roccamo, Ana Maria. 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; ArgentinaXXX Reunión Anual de la Sociedad Argentina de Investigación en NeurocienciasMar del PlataArgentinaSociedad Argentina de Investigación en NeurocienciasSociedad Argentina de Investigación en Neurociencias2015info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/conferenceObjectReuniónBookhttp://purl.org/coar/resource_type/c_5794info:ar-repo/semantics/documentoDeConferenciaapplication/pdfapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/237764Mimicking Human Myasthenic Syndromes in C. elegans: Evaluation of Function and Drug Modulation of Nicotinic Receptors; XXX Reunión Anual de la Sociedad Argentina de Investigación en Neurociencias; Mar del Plata; Argentina; 2015; 330-330CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://saneurociencias.org.ar/wp-content/uploads/2022/01/SAN2015_Mar-del-Plata._libro-de-resumenes.pdfNacionalinfo:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-03T09:47:30Zoai:ri.conicet.gov.ar:11336/237764instacron: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 09:47:30.396CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Mimicking Human Myasthenic Syndromes in C. elegans: Evaluation of Function and Drug Modulation of Nicotinic Receptors
title Mimicking Human Myasthenic Syndromes in C. elegans: Evaluation of Function and Drug Modulation of Nicotinic Receptors
spellingShingle Mimicking Human Myasthenic Syndromes in C. elegans: Evaluation of Function and Drug Modulation of Nicotinic Receptors
Bergé, Ignacio
SCMS
PATCH-CLAMP
C.-ELEGANS
title_short Mimicking Human Myasthenic Syndromes in C. elegans: Evaluation of Function and Drug Modulation of Nicotinic Receptors
title_full Mimicking Human Myasthenic Syndromes in C. elegans: Evaluation of Function and Drug Modulation of Nicotinic Receptors
title_fullStr Mimicking Human Myasthenic Syndromes in C. elegans: Evaluation of Function and Drug Modulation of Nicotinic Receptors
title_full_unstemmed Mimicking Human Myasthenic Syndromes in C. elegans: Evaluation of Function and Drug Modulation of Nicotinic Receptors
title_sort Mimicking Human Myasthenic Syndromes in C. elegans: Evaluation of Function and Drug Modulation of Nicotinic Receptors
dc.creator.none.fl_str_mv Bergé, Ignacio
Hernando, Guillermina Silvana
Andreocci, Emanuel
Roccamo, Ana Maria
Bouzat, Cecilia Beatriz
author Bergé, Ignacio
author_facet Bergé, Ignacio
Hernando, Guillermina Silvana
Andreocci, Emanuel
Roccamo, Ana Maria
Bouzat, Cecilia Beatriz
author_role author
author2 Hernando, Guillermina Silvana
Andreocci, Emanuel
Roccamo, Ana Maria
Bouzat, Cecilia Beatriz
author2_role author
author
author
author
dc.subject.none.fl_str_mv SCMS
PATCH-CLAMP
C.-ELEGANS
topic SCMS
PATCH-CLAMP
C.-ELEGANS
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.6
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv In humans, gain-of-function mutations in the muscle nicotinic receptor (AChR) lead to slowchannel congenital myasthenic syndromes (SCCMS), characterized by slow decay of endplate currents, destabilization of the closed channel and prolonged activation episodes of AChR. Our goal is to use the free-living nematode C. elegans to generate models of these human syndromes. To this end, we first generated transgenic worms expressing mutant LAChRs at 9' position of the M2 segment, which has been shown to form the gate of the ion channel in vertebrates. Electrophysiological recordings of L-AChRs from muscle cells of these transgenic worms show an increase of 11- to 14-fold of the open-channel lifetime and decreased desensitization rate with respect to wild-type, as expected for a gain-offunction mutation. We found that quinidine sulfate, a long-lived open-channel blocker of the human AChR used for the treatment of SCCMS, also reduces the open duration of the mutant C. elegans L-AChR. These results show that it is possible to mimic in C. elegans the molecular and functional changes observed in human AChRs as well as their responses to therapeutic drugs. We next generated mutant strains with L-AChRs mimicking gain-offunction mutations that lead to severe slow-channel CMS to be used as models of these human neuromuscular disorders for drug screening and development of therapeutic strategies
Fil: Bergé, Ignacio. 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: Andreocci, Emanuel. 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: Roccamo, Ana Maria. 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
XXX Reunión Anual de la Sociedad Argentina de Investigación en Neurociencias
Mar del Plata
Argentina
Sociedad Argentina de Investigación en Neurociencias
description In humans, gain-of-function mutations in the muscle nicotinic receptor (AChR) lead to slowchannel congenital myasthenic syndromes (SCCMS), characterized by slow decay of endplate currents, destabilization of the closed channel and prolonged activation episodes of AChR. Our goal is to use the free-living nematode C. elegans to generate models of these human syndromes. To this end, we first generated transgenic worms expressing mutant LAChRs at 9' position of the M2 segment, which has been shown to form the gate of the ion channel in vertebrates. Electrophysiological recordings of L-AChRs from muscle cells of these transgenic worms show an increase of 11- to 14-fold of the open-channel lifetime and decreased desensitization rate with respect to wild-type, as expected for a gain-offunction mutation. We found that quinidine sulfate, a long-lived open-channel blocker of the human AChR used for the treatment of SCCMS, also reduces the open duration of the mutant C. elegans L-AChR. These results show that it is possible to mimic in C. elegans the molecular and functional changes observed in human AChRs as well as their responses to therapeutic drugs. We next generated mutant strains with L-AChRs mimicking gain-offunction mutations that lead to severe slow-channel CMS to be used as models of these human neuromuscular disorders for drug screening and development of therapeutic strategies
publishDate 2015
dc.date.none.fl_str_mv 2015
dc.type.none.fl_str_mv info:eu-repo/semantics/publishedVersion
info:eu-repo/semantics/conferenceObject
Reunión
Book
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/11336/237764
Mimicking Human Myasthenic Syndromes in C. elegans: Evaluation of Function and Drug Modulation of Nicotinic Receptors; XXX Reunión Anual de la Sociedad Argentina de Investigación en Neurociencias; Mar del Plata; Argentina; 2015; 330-330
CONICET Digital
CONICET
url http://hdl.handle.net/11336/237764
identifier_str_mv Mimicking Human Myasthenic Syndromes in C. elegans: Evaluation of Function and Drug Modulation of Nicotinic Receptors; XXX Reunión Anual de la Sociedad Argentina de Investigación en Neurociencias; Mar del Plata; Argentina; 2015; 330-330
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://saneurociencias.org.ar/wp-content/uploads/2022/01/SAN2015_Mar-del-Plata._libro-de-resumenes.pdf
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 Nacional
dc.publisher.none.fl_str_mv Sociedad Argentina de Investigación en Neurociencias
publisher.none.fl_str_mv Sociedad Argentina de Investigación en Neurociencias
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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