Gain-of-function mutations in Caenorhabditis elegans levamisole-sensitive nicotinic receptors evaluated at the single-channel level

Autores
Bergé, Ignacio; Hernando, Guillermina Silvana; Bouzat, Cecilia Beatriz
Año de publicación
2025
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
The nematode Caenorhabditis elegans is a valuable model for studying both human neuromuscular disorders and parasitic nematodes. Notably, it expresses one of the largest families of nicotinic acetylcholine receptors (nAChRs), pentameric ligand-gated ion channels that mediate synaptic transmission. At the neuromuscular junction, the primary excitatory receptor is the levamisole-sensitive AChR (L-AChR). We investigated gain-of-function mutations in the L-AChR pore-lining TM2 domain, some of which mimic those causing human slow-channel congenital myasthenic syndromes (CMS). Using null mutants lacking essential subunits UNC-38 or UNC-29, we reintroduced these subunits carrying specific mutations and performed single-channel recordings from C. elegans cultured muscle cells. Wild-type receptors display brief, isolated openings, whereas TM2 9′ mutants exhibit prolonged openings and extended activation episodes, underscoring the conserved functional role of this position across species. Additional mutations in other TM2 residues linked to human CMS similarly increase channel open time, recapitulating pathological gating behavior observed in patients. Quinidine sulfate, a therapeutic agent used to treat slow-channel CMS, reduced the abnormally prolonged channel openings of mutant L-AChRs. These findings demonstrate the evolutionary conservation of TM2 residues in nAChR activation, validate C. elegans as a model for human channelopathies, and support its use in exploring therapeutic interventions for nAChR-related disorders.
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. 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: 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 RECEPTOR (NACHR)
PATCH-CLAMP
ELECTROPHYSIOLOGY
CAENORHABDITIS ELEGANS
LIGAND-GATED ION CHANNELS
Nivel de accesibilidad
acceso embargado
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:11336/271167
Acceder
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oai_identifier_str oai:ri.conicet.gov.ar:11336/271167
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Gain-of-function mutations in Caenorhabditis elegans levamisole-sensitive nicotinic receptors evaluated at the single-channel levelBergé, IgnacioHernando, Guillermina SilvanaBouzat, Cecilia BeatrizNICOTINIC ACETYLCHOLINE RECEPTOR (NACHR)PATCH-CLAMPELECTROPHYSIOLOGYCAENORHABDITIS ELEGANSLIGAND-GATED ION CHANNELShttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1The nematode Caenorhabditis elegans is a valuable model for studying both human neuromuscular disorders and parasitic nematodes. Notably, it expresses one of the largest families of nicotinic acetylcholine receptors (nAChRs), pentameric ligand-gated ion channels that mediate synaptic transmission. At the neuromuscular junction, the primary excitatory receptor is the levamisole-sensitive AChR (L-AChR). We investigated gain-of-function mutations in the L-AChR pore-lining TM2 domain, some of which mimic those causing human slow-channel congenital myasthenic syndromes (CMS). Using null mutants lacking essential subunits UNC-38 or UNC-29, we reintroduced these subunits carrying specific mutations and performed single-channel recordings from C. elegans cultured muscle cells. Wild-type receptors display brief, isolated openings, whereas TM2 9′ mutants exhibit prolonged openings and extended activation episodes, underscoring the conserved functional role of this position across species. Additional mutations in other TM2 residues linked to human CMS similarly increase channel open time, recapitulating pathological gating behavior observed in patients. Quinidine sulfate, a therapeutic agent used to treat slow-channel CMS, reduced the abnormally prolonged channel openings of mutant L-AChRs. These findings demonstrate the evolutionary conservation of TM2 residues in nAChR activation, validate C. elegans as a model for human channelopathies, and support its use in exploring therapeutic interventions for nAChR-related disorders.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. 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: 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; ArgentinaAcademic Press Inc Elsevier Science2025-07-23info:eu-repo/date/embargoEnd/2026-09-30info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/271167Bergé, Ignacio; Hernando, Guillermina Silvana; Bouzat, Cecilia Beatriz; Gain-of-function mutations in Caenorhabditis elegans levamisole-sensitive nicotinic receptors evaluated at the single-channel level; Academic Press Inc Elsevier Science; Biochemical and Biophysical Research Communications; 778; 152401; 23-7-2025; 1-90006-291XCONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://www.sciencedirect.com/science/article/abs/pii/S0006291X25011167info:eu-repo/semantics/altIdentifier/doi/10.1016/j.bbrc.2025.152401info:eu-repo/semantics/embargoedAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-29T09:55:05Zoai:ri.conicet.gov.ar:11336/271167instacron: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 09:55:05.852CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Gain-of-function mutations in Caenorhabditis elegans levamisole-sensitive nicotinic receptors evaluated at the single-channel level
title Gain-of-function mutations in Caenorhabditis elegans levamisole-sensitive nicotinic receptors evaluated at the single-channel level
spellingShingle Gain-of-function mutations in Caenorhabditis elegans levamisole-sensitive nicotinic receptors evaluated at the single-channel level
Bergé, Ignacio
NICOTINIC ACETYLCHOLINE RECEPTOR (NACHR)
PATCH-CLAMP
ELECTROPHYSIOLOGY
CAENORHABDITIS ELEGANS
LIGAND-GATED ION CHANNELS
title_short Gain-of-function mutations in Caenorhabditis elegans levamisole-sensitive nicotinic receptors evaluated at the single-channel level
title_full Gain-of-function mutations in Caenorhabditis elegans levamisole-sensitive nicotinic receptors evaluated at the single-channel level
title_fullStr Gain-of-function mutations in Caenorhabditis elegans levamisole-sensitive nicotinic receptors evaluated at the single-channel level
title_full_unstemmed Gain-of-function mutations in Caenorhabditis elegans levamisole-sensitive nicotinic receptors evaluated at the single-channel level
title_sort Gain-of-function mutations in Caenorhabditis elegans levamisole-sensitive nicotinic receptors evaluated at the single-channel level
dc.creator.none.fl_str_mv Bergé, Ignacio
Hernando, Guillermina Silvana
Bouzat, Cecilia Beatriz
author Bergé, Ignacio
author_facet Bergé, Ignacio
Hernando, Guillermina Silvana
Bouzat, Cecilia Beatriz
author_role author
author2 Hernando, Guillermina Silvana
Bouzat, Cecilia Beatriz
author2_role author
author
dc.subject.none.fl_str_mv NICOTINIC ACETYLCHOLINE RECEPTOR (NACHR)
PATCH-CLAMP
ELECTROPHYSIOLOGY
CAENORHABDITIS ELEGANS
LIGAND-GATED ION CHANNELS
topic NICOTINIC ACETYLCHOLINE RECEPTOR (NACHR)
PATCH-CLAMP
ELECTROPHYSIOLOGY
CAENORHABDITIS ELEGANS
LIGAND-GATED ION CHANNELS
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.6
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv The nematode Caenorhabditis elegans is a valuable model for studying both human neuromuscular disorders and parasitic nematodes. Notably, it expresses one of the largest families of nicotinic acetylcholine receptors (nAChRs), pentameric ligand-gated ion channels that mediate synaptic transmission. At the neuromuscular junction, the primary excitatory receptor is the levamisole-sensitive AChR (L-AChR). We investigated gain-of-function mutations in the L-AChR pore-lining TM2 domain, some of which mimic those causing human slow-channel congenital myasthenic syndromes (CMS). Using null mutants lacking essential subunits UNC-38 or UNC-29, we reintroduced these subunits carrying specific mutations and performed single-channel recordings from C. elegans cultured muscle cells. Wild-type receptors display brief, isolated openings, whereas TM2 9′ mutants exhibit prolonged openings and extended activation episodes, underscoring the conserved functional role of this position across species. Additional mutations in other TM2 residues linked to human CMS similarly increase channel open time, recapitulating pathological gating behavior observed in patients. Quinidine sulfate, a therapeutic agent used to treat slow-channel CMS, reduced the abnormally prolonged channel openings of mutant L-AChRs. These findings demonstrate the evolutionary conservation of TM2 residues in nAChR activation, validate C. elegans as a model for human channelopathies, and support its use in exploring therapeutic interventions for nAChR-related disorders.
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. 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: 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 The nematode Caenorhabditis elegans is a valuable model for studying both human neuromuscular disorders and parasitic nematodes. Notably, it expresses one of the largest families of nicotinic acetylcholine receptors (nAChRs), pentameric ligand-gated ion channels that mediate synaptic transmission. At the neuromuscular junction, the primary excitatory receptor is the levamisole-sensitive AChR (L-AChR). We investigated gain-of-function mutations in the L-AChR pore-lining TM2 domain, some of which mimic those causing human slow-channel congenital myasthenic syndromes (CMS). Using null mutants lacking essential subunits UNC-38 or UNC-29, we reintroduced these subunits carrying specific mutations and performed single-channel recordings from C. elegans cultured muscle cells. Wild-type receptors display brief, isolated openings, whereas TM2 9′ mutants exhibit prolonged openings and extended activation episodes, underscoring the conserved functional role of this position across species. Additional mutations in other TM2 residues linked to human CMS similarly increase channel open time, recapitulating pathological gating behavior observed in patients. Quinidine sulfate, a therapeutic agent used to treat slow-channel CMS, reduced the abnormally prolonged channel openings of mutant L-AChRs. These findings demonstrate the evolutionary conservation of TM2 residues in nAChR activation, validate C. elegans as a model for human channelopathies, and support its use in exploring therapeutic interventions for nAChR-related disorders.
publishDate 2025
dc.date.none.fl_str_mv 2025-07-23
info:eu-repo/date/embargoEnd/2026-09-30
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/11336/271167
Bergé, Ignacio; Hernando, Guillermina Silvana; Bouzat, Cecilia Beatriz; Gain-of-function mutations in Caenorhabditis elegans levamisole-sensitive nicotinic receptors evaluated at the single-channel level; Academic Press Inc Elsevier Science; Biochemical and Biophysical Research Communications; 778; 152401; 23-7-2025; 1-9
0006-291X
CONICET Digital
CONICET
url http://hdl.handle.net/11336/271167
identifier_str_mv Bergé, Ignacio; Hernando, Guillermina Silvana; Bouzat, Cecilia Beatriz; Gain-of-function mutations in Caenorhabditis elegans levamisole-sensitive nicotinic receptors evaluated at the single-channel level; Academic Press Inc Elsevier Science; Biochemical and Biophysical Research Communications; 778; 152401; 23-7-2025; 1-9
0006-291X
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.sciencedirect.com/science/article/abs/pii/S0006291X25011167
info:eu-repo/semantics/altIdentifier/doi/10.1016/j.bbrc.2025.152401
dc.rights.none.fl_str_mv info:eu-repo/semantics/embargoedAccess
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
eu_rights_str_mv embargoedAccess
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
dc.publisher.none.fl_str_mv Academic Press Inc Elsevier Science
publisher.none.fl_str_mv Academic Press Inc Elsevier Science
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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score 13.070432

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