Differential Pharmacological Activity of JN403 between á7 and Muscle Nicotinic Acetylcholine Receptors

Autores
Arias, Hugo Ruben; de Rosa, Maria Jose; Bergé, Ignacio; Feuerbach, Dominik; Bouzat, Cecilia Beatriz
Año de publicación
2013
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
The differential action of the novel agonist JN403 at neuronalα7 and muscle nicotinic receptors (AChRs)was explored by using a combination of functional and structural approaches. Single-channel recordings reveal that JN403 is a potent agonist of α7 but a very low-efficacy agonist of muscle AChRs. JN403 elicits detectable openings of α7 and muscle AChRs at concentrations∼1000-fold lower and∼20-fold higher, respectively, than that for ACh. Single-channel activity elicited by JN403 is very similar to that elicited by ACh in α7 but profoundly different in muscle AChRs, where openings are brief and infrequent and do not appear in clusters at any concentration. JN403 elicits single-channel activity of muscle AChRs lacking theεsubunit, with opening events being more frequent and prolonged than those of wild-type AChRs. This finding is in line with the molecular docking studies predicting that JN403 may form a hydrogen bond required for potent activation at the α−δ but not at the α−ε binding site. JN403 does not elicit detectable Ca2+ influx in muscle AChRs but inhibits (±)-epibatidine-elicited influx mainly by a noncompetitive mechanism. Such inhibition is compatible with single-channel recordings revealing that JN403 produces open-channel blockade and early termination of ACh-elicited clusters, and it is therefore also a potent desensitizing enhancer of muscle AChRs. The latter mechanism is supported by the JN403-induced increase in the level of binding of [3H]cytisine and [3H]TCP to resting AChRs. Elucidation of the differences in activity of JN403 between neuronal α7 and muscle AChRs provides further insights into mechanisms underlying selectivity for α7 AChRs.
Fil: Arias, Hugo Ruben. California Northstate University College of Medicine; Estados Unidos
Fil: de Rosa, Maria Jose. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico CONICET Bahía Blanca. Instituto de Investigaciones Bioquímicas Bahía Blanca (i); Argentina
Fil: Bergé, Ignacio. Consejo Nacional de Investigaciones Cientificas y Tecnicas. Centro Cientifico Tecnol.conicet - Bahia Blanca. Instituto de Invest.bioquimicas Bahia Blanca (i); Argentina
Fil: Feuerbach, Dominik. Novartis Institutes for Biomedical Research; Suiza
Fil: Bouzat, Cecilia Beatriz. Consejo Nacional de Investigaciones Cientificas y Tecnicas. Centro Cientifico Tecnol.conicet - Bahia Blanca. Instituto de Invest.bioquimicas Bahia Blanca (i); Argentina
Materia
Receptor Nicotinico
Agonista
Patch Clamp
Receptor Cys-Loop
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-nd/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/4538
Acceder
id CONICETDig_75adf7bc88931e35dea8acd768e0754d
oai_identifier_str oai:ri.conicet.gov.ar:11336/4538
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Differential Pharmacological Activity of JN403 between á7 and Muscle Nicotinic Acetylcholine ReceptorsArias, Hugo Rubende Rosa, Maria JoseBergé, IgnacioFeuerbach, DominikBouzat, Cecilia BeatrizReceptor NicotinicoAgonistaPatch ClampReceptor Cys-Loophttps://purl.org/becyt/ford/3.1https://purl.org/becyt/ford/3The differential action of the novel agonist JN403 at neuronalα7 and muscle nicotinic receptors (AChRs)was explored by using a combination of functional and structural approaches. Single-channel recordings reveal that JN403 is a potent agonist of α7 but a very low-efficacy agonist of muscle AChRs. JN403 elicits detectable openings of α7 and muscle AChRs at concentrations∼1000-fold lower and∼20-fold higher, respectively, than that for ACh. Single-channel activity elicited by JN403 is very similar to that elicited by ACh in α7 but profoundly different in muscle AChRs, where openings are brief and infrequent and do not appear in clusters at any concentration. JN403 elicits single-channel activity of muscle AChRs lacking theεsubunit, with opening events being more frequent and prolonged than those of wild-type AChRs. This finding is in line with the molecular docking studies predicting that JN403 may form a hydrogen bond required for potent activation at the α−δ but not at the α−ε binding site. JN403 does not elicit detectable Ca2+ influx in muscle AChRs but inhibits (±)-epibatidine-elicited influx mainly by a noncompetitive mechanism. Such inhibition is compatible with single-channel recordings revealing that JN403 produces open-channel blockade and early termination of ACh-elicited clusters, and it is therefore also a potent desensitizing enhancer of muscle AChRs. The latter mechanism is supported by the JN403-induced increase in the level of binding of [3H]cytisine and [3H]TCP to resting AChRs. Elucidation of the differences in activity of JN403 between neuronal α7 and muscle AChRs provides further insights into mechanisms underlying selectivity for α7 AChRs.Fil: Arias, Hugo Ruben. California Northstate University College of Medicine; Estados UnidosFil: de Rosa, Maria Jose. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico CONICET Bahía Blanca. Instituto de Investigaciones Bioquímicas Bahía Blanca (i); ArgentinaFil: Bergé, Ignacio. Consejo Nacional de Investigaciones Cientificas y Tecnicas. Centro Cientifico Tecnol.conicet - Bahia Blanca. Instituto de Invest.bioquimicas Bahia Blanca (i); ArgentinaFil: Feuerbach, Dominik. Novartis Institutes for Biomedical Research; SuizaFil: Bouzat, Cecilia Beatriz. Consejo Nacional de Investigaciones Cientificas y Tecnicas. Centro Cientifico Tecnol.conicet - Bahia Blanca. Instituto de Invest.bioquimicas Bahia Blanca (i); ArgentinaAmerican Chemical Society2013-10info: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/11336/4538Arias, Hugo Ruben; de Rosa, Maria Jose; Bergé, Ignacio; Feuerbach, Dominik; Bouzat, Cecilia Beatriz; Differential Pharmacological Activity of JN403 between á7 and Muscle Nicotinic Acetylcholine Receptors; American Chemical Society; Biochemistry; 52; 10-2013; 8480-84880006-2960enginfo:eu-repo/semantics/altIdentifier/doi/info:eu-repo/semantics/altIdentifier/url/http://www.ncbi.nlm.nih.gov/pubmed/24164482info:eu-repo/semantics/altIdentifier/doi/10.1021/bi4012572info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-nd/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-29T09:46:44Zoai:ri.conicet.gov.ar:11336/4538instacron: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 09:46:44.37CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Differential Pharmacological Activity of JN403 between á7 and Muscle Nicotinic Acetylcholine Receptors
title Differential Pharmacological Activity of JN403 between á7 and Muscle Nicotinic Acetylcholine Receptors
spellingShingle Differential Pharmacological Activity of JN403 between á7 and Muscle Nicotinic Acetylcholine Receptors
Arias, Hugo Ruben
Receptor Nicotinico
Agonista
Patch Clamp
Receptor Cys-Loop
title_short Differential Pharmacological Activity of JN403 between á7 and Muscle Nicotinic Acetylcholine Receptors
title_full Differential Pharmacological Activity of JN403 between á7 and Muscle Nicotinic Acetylcholine Receptors
title_fullStr Differential Pharmacological Activity of JN403 between á7 and Muscle Nicotinic Acetylcholine Receptors
title_full_unstemmed Differential Pharmacological Activity of JN403 between á7 and Muscle Nicotinic Acetylcholine Receptors
title_sort Differential Pharmacological Activity of JN403 between á7 and Muscle Nicotinic Acetylcholine Receptors
dc.creator.none.fl_str_mv Arias, Hugo Ruben
de Rosa, Maria Jose
Bergé, Ignacio
Feuerbach, Dominik
Bouzat, Cecilia Beatriz
author Arias, Hugo Ruben
author_facet Arias, Hugo Ruben
de Rosa, Maria Jose
Bergé, Ignacio
Feuerbach, Dominik
Bouzat, Cecilia Beatriz
author_role author
author2 de Rosa, Maria Jose
Bergé, Ignacio
Feuerbach, Dominik
Bouzat, Cecilia Beatriz
author2_role author
author
author
author
dc.subject.none.fl_str_mv Receptor Nicotinico
Agonista
Patch Clamp
Receptor Cys-Loop
topic Receptor Nicotinico
Agonista
Patch Clamp
Receptor Cys-Loop
purl_subject.fl_str_mv https://purl.org/becyt/ford/3.1
https://purl.org/becyt/ford/3
dc.description.none.fl_txt_mv The differential action of the novel agonist JN403 at neuronalα7 and muscle nicotinic receptors (AChRs)was explored by using a combination of functional and structural approaches. Single-channel recordings reveal that JN403 is a potent agonist of α7 but a very low-efficacy agonist of muscle AChRs. JN403 elicits detectable openings of α7 and muscle AChRs at concentrations∼1000-fold lower and∼20-fold higher, respectively, than that for ACh. Single-channel activity elicited by JN403 is very similar to that elicited by ACh in α7 but profoundly different in muscle AChRs, where openings are brief and infrequent and do not appear in clusters at any concentration. JN403 elicits single-channel activity of muscle AChRs lacking theεsubunit, with opening events being more frequent and prolonged than those of wild-type AChRs. This finding is in line with the molecular docking studies predicting that JN403 may form a hydrogen bond required for potent activation at the α−δ but not at the α−ε binding site. JN403 does not elicit detectable Ca2+ influx in muscle AChRs but inhibits (±)-epibatidine-elicited influx mainly by a noncompetitive mechanism. Such inhibition is compatible with single-channel recordings revealing that JN403 produces open-channel blockade and early termination of ACh-elicited clusters, and it is therefore also a potent desensitizing enhancer of muscle AChRs. The latter mechanism is supported by the JN403-induced increase in the level of binding of [3H]cytisine and [3H]TCP to resting AChRs. Elucidation of the differences in activity of JN403 between neuronal α7 and muscle AChRs provides further insights into mechanisms underlying selectivity for α7 AChRs.
Fil: Arias, Hugo Ruben. California Northstate University College of Medicine; Estados Unidos
Fil: de Rosa, Maria Jose. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico CONICET Bahía Blanca. Instituto de Investigaciones Bioquímicas Bahía Blanca (i); Argentina
Fil: Bergé, Ignacio. Consejo Nacional de Investigaciones Cientificas y Tecnicas. Centro Cientifico Tecnol.conicet - Bahia Blanca. Instituto de Invest.bioquimicas Bahia Blanca (i); Argentina
Fil: Feuerbach, Dominik. Novartis Institutes for Biomedical Research; Suiza
Fil: Bouzat, Cecilia Beatriz. Consejo Nacional de Investigaciones Cientificas y Tecnicas. Centro Cientifico Tecnol.conicet - Bahia Blanca. Instituto de Invest.bioquimicas Bahia Blanca (i); Argentina
description The differential action of the novel agonist JN403 at neuronalα7 and muscle nicotinic receptors (AChRs)was explored by using a combination of functional and structural approaches. Single-channel recordings reveal that JN403 is a potent agonist of α7 but a very low-efficacy agonist of muscle AChRs. JN403 elicits detectable openings of α7 and muscle AChRs at concentrations∼1000-fold lower and∼20-fold higher, respectively, than that for ACh. Single-channel activity elicited by JN403 is very similar to that elicited by ACh in α7 but profoundly different in muscle AChRs, where openings are brief and infrequent and do not appear in clusters at any concentration. JN403 elicits single-channel activity of muscle AChRs lacking theεsubunit, with opening events being more frequent and prolonged than those of wild-type AChRs. This finding is in line with the molecular docking studies predicting that JN403 may form a hydrogen bond required for potent activation at the α−δ but not at the α−ε binding site. JN403 does not elicit detectable Ca2+ influx in muscle AChRs but inhibits (±)-epibatidine-elicited influx mainly by a noncompetitive mechanism. Such inhibition is compatible with single-channel recordings revealing that JN403 produces open-channel blockade and early termination of ACh-elicited clusters, and it is therefore also a potent desensitizing enhancer of muscle AChRs. The latter mechanism is supported by the JN403-induced increase in the level of binding of [3H]cytisine and [3H]TCP to resting AChRs. Elucidation of the differences in activity of JN403 between neuronal α7 and muscle AChRs provides further insights into mechanisms underlying selectivity for α7 AChRs.
publishDate 2013
dc.date.none.fl_str_mv 2013-10
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/11336/4538
Arias, Hugo Ruben; de Rosa, Maria Jose; Bergé, Ignacio; Feuerbach, Dominik; Bouzat, Cecilia Beatriz; Differential Pharmacological Activity of JN403 between á7 and Muscle Nicotinic Acetylcholine Receptors; American Chemical Society; Biochemistry; 52; 10-2013; 8480-8488
0006-2960
url http://hdl.handle.net/11336/4538
identifier_str_mv Arias, Hugo Ruben; de Rosa, Maria Jose; Bergé, Ignacio; Feuerbach, Dominik; Bouzat, Cecilia Beatriz; Differential Pharmacological Activity of JN403 between á7 and Muscle Nicotinic Acetylcholine Receptors; American Chemical Society; Biochemistry; 52; 10-2013; 8480-8488
0006-2960
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/doi/
info:eu-repo/semantics/altIdentifier/url/http://www.ncbi.nlm.nih.gov/pubmed/24164482
info:eu-repo/semantics/altIdentifier/doi/10.1021/bi4012572
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc-nd/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-nd/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
application/pdf
application/pdf
dc.publisher.none.fl_str_mv American Chemical Society
publisher.none.fl_str_mv American Chemical Society
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 13.069144

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