Exploring the positive allosteric modulation of human α7 nicotinic receptors from a single-channel perspective
- Autores
- Andersen, Natalia Denise; Nielsen, Beatriz Elizabeth; Corradi, Jeremias; Tolosa, María Fernanda; Feuerbach, Dominik; Arias, Hugo Rubén; Bouzat, Cecilia Beatriz
- Año de publicación
- 2016
- Idioma
- inglés
- Tipo de recurso
- artículo
- Estado
- versión publicada
- Descripción
- Enhancement of α7 nicotinic receptor (nAChR) function by positive allosteric modulators (PAMs) is a promising therapeutic strategy to improve cognitive deficits. PAMs have been classified only on the basis of their macroscopic effects as type I, which only enhance agonist-induced currents, and type II, which also decrease desensitization and reactivate desensitized nAChRs. To decipher the molecular basis underlying these distinct activities, we explored the effects on single-α7 channel currents of representative members of each type and of less characterized compounds. Our results reveal that all PAMs enhance open-channel lifetime and produce episodes of successive openings, thus indicating that both types affect α7 kinetics. Different PAM types show different sensitivity to temperature, suggesting different mechanisms of potentiation. By using a mutant α7 receptor that is insensitive to the prototype type II PAM (PNU-120596), we show that some though not all type I PAMs share the structural determinants of potentiation. Overall, our study provides novel information on α7 potentiation, which is key to the ongoing development of therapeutic compounds.
Fil: Andersen, Natalia Denise. 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: Nielsen, Beatriz Elizabeth. 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: 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
Fil: Tolosa, María Fernanda. 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: Feuerbach, Dominik. Novartis Institutes For Biomedical Research; Suiza
Fil: Arias, Hugo Rubén. California Northstate University College Of Medicine; Estados Unidos
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 - Materia
-
Cys-Loop Receptors
Nicotinic Receptors
Patch-Clamp
Positive Allosteric Modulators
Single-Channel Recordings - Nivel de accesibilidad
- acceso abierto
- Condiciones de uso
- https://creativecommons.org/licenses/by-nc-nd/2.5/ar/
- Repositorio
- Institución
- Consejo Nacional de Investigaciones Científicas y Técnicas
- OAI Identificador
- oai:ri.conicet.gov.ar:11336/38702
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Exploring the positive allosteric modulation of human α7 nicotinic receptors from a single-channel perspectiveAndersen, Natalia DeniseNielsen, Beatriz ElizabethCorradi, JeremiasTolosa, María FernandaFeuerbach, DominikArias, Hugo RubénBouzat, Cecilia BeatrizCys-Loop ReceptorsNicotinic ReceptorsPatch-ClampPositive Allosteric ModulatorsSingle-Channel Recordingshttps://purl.org/becyt/ford/3.1https://purl.org/becyt/ford/3Enhancement of α7 nicotinic receptor (nAChR) function by positive allosteric modulators (PAMs) is a promising therapeutic strategy to improve cognitive deficits. PAMs have been classified only on the basis of their macroscopic effects as type I, which only enhance agonist-induced currents, and type II, which also decrease desensitization and reactivate desensitized nAChRs. To decipher the molecular basis underlying these distinct activities, we explored the effects on single-α7 channel currents of representative members of each type and of less characterized compounds. Our results reveal that all PAMs enhance open-channel lifetime and produce episodes of successive openings, thus indicating that both types affect α7 kinetics. Different PAM types show different sensitivity to temperature, suggesting different mechanisms of potentiation. By using a mutant α7 receptor that is insensitive to the prototype type II PAM (PNU-120596), we show that some though not all type I PAMs share the structural determinants of potentiation. Overall, our study provides novel information on α7 potentiation, which is key to the ongoing development of therapeutic compounds.Fil: Andersen, Natalia Denise. 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: Nielsen, Beatriz Elizabeth. 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: 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; ArgentinaFil: Tolosa, María Fernanda. 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: Feuerbach, Dominik. Novartis Institutes For Biomedical Research; SuizaFil: Arias, Hugo Rubén. California Northstate University College Of Medicine; Estados UnidosFil: 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; ArgentinaPergamon-Elsevier Science Ltd2016-08info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/38702Andersen, Natalia Denise; Nielsen, Beatriz Elizabeth; Corradi, Jeremias; Tolosa, María Fernanda; Feuerbach, Dominik; et al.; Exploring the positive allosteric modulation of human α7 nicotinic receptors from a single-channel perspective; Pergamon-Elsevier Science Ltd; Neuropharmacology; 107; 8-2016; 189-2000028-3908CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/http://www.sciencedirect.com/science/article/pii/S0028390816300673info:eu-repo/semantics/altIdentifier/doi/10.1016/j.neuropharm.2016.02.032info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-nd/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-03T10:11:21Zoai:ri.conicet.gov.ar:11336/38702instacron: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 10:11:22.175CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse |
dc.title.none.fl_str_mv |
Exploring the positive allosteric modulation of human α7 nicotinic receptors from a single-channel perspective |
title |
Exploring the positive allosteric modulation of human α7 nicotinic receptors from a single-channel perspective |
spellingShingle |
Exploring the positive allosteric modulation of human α7 nicotinic receptors from a single-channel perspective Andersen, Natalia Denise Cys-Loop Receptors Nicotinic Receptors Patch-Clamp Positive Allosteric Modulators Single-Channel Recordings |
title_short |
Exploring the positive allosteric modulation of human α7 nicotinic receptors from a single-channel perspective |
title_full |
Exploring the positive allosteric modulation of human α7 nicotinic receptors from a single-channel perspective |
title_fullStr |
Exploring the positive allosteric modulation of human α7 nicotinic receptors from a single-channel perspective |
title_full_unstemmed |
Exploring the positive allosteric modulation of human α7 nicotinic receptors from a single-channel perspective |
title_sort |
Exploring the positive allosteric modulation of human α7 nicotinic receptors from a single-channel perspective |
dc.creator.none.fl_str_mv |
Andersen, Natalia Denise Nielsen, Beatriz Elizabeth Corradi, Jeremias Tolosa, María Fernanda Feuerbach, Dominik Arias, Hugo Rubén Bouzat, Cecilia Beatriz |
author |
Andersen, Natalia Denise |
author_facet |
Andersen, Natalia Denise Nielsen, Beatriz Elizabeth Corradi, Jeremias Tolosa, María Fernanda Feuerbach, Dominik Arias, Hugo Rubén Bouzat, Cecilia Beatriz |
author_role |
author |
author2 |
Nielsen, Beatriz Elizabeth Corradi, Jeremias Tolosa, María Fernanda Feuerbach, Dominik Arias, Hugo Rubén Bouzat, Cecilia Beatriz |
author2_role |
author author author author author author |
dc.subject.none.fl_str_mv |
Cys-Loop Receptors Nicotinic Receptors Patch-Clamp Positive Allosteric Modulators Single-Channel Recordings |
topic |
Cys-Loop Receptors Nicotinic Receptors Patch-Clamp Positive Allosteric Modulators Single-Channel Recordings |
purl_subject.fl_str_mv |
https://purl.org/becyt/ford/3.1 https://purl.org/becyt/ford/3 |
dc.description.none.fl_txt_mv |
Enhancement of α7 nicotinic receptor (nAChR) function by positive allosteric modulators (PAMs) is a promising therapeutic strategy to improve cognitive deficits. PAMs have been classified only on the basis of their macroscopic effects as type I, which only enhance agonist-induced currents, and type II, which also decrease desensitization and reactivate desensitized nAChRs. To decipher the molecular basis underlying these distinct activities, we explored the effects on single-α7 channel currents of representative members of each type and of less characterized compounds. Our results reveal that all PAMs enhance open-channel lifetime and produce episodes of successive openings, thus indicating that both types affect α7 kinetics. Different PAM types show different sensitivity to temperature, suggesting different mechanisms of potentiation. By using a mutant α7 receptor that is insensitive to the prototype type II PAM (PNU-120596), we show that some though not all type I PAMs share the structural determinants of potentiation. Overall, our study provides novel information on α7 potentiation, which is key to the ongoing development of therapeutic compounds. Fil: Andersen, Natalia Denise. 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: Nielsen, Beatriz Elizabeth. 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: 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 Fil: Tolosa, María Fernanda. 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: Feuerbach, Dominik. Novartis Institutes For Biomedical Research; Suiza Fil: Arias, Hugo Rubén. California Northstate University College Of Medicine; Estados Unidos 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 |
description |
Enhancement of α7 nicotinic receptor (nAChR) function by positive allosteric modulators (PAMs) is a promising therapeutic strategy to improve cognitive deficits. PAMs have been classified only on the basis of their macroscopic effects as type I, which only enhance agonist-induced currents, and type II, which also decrease desensitization and reactivate desensitized nAChRs. To decipher the molecular basis underlying these distinct activities, we explored the effects on single-α7 channel currents of representative members of each type and of less characterized compounds. Our results reveal that all PAMs enhance open-channel lifetime and produce episodes of successive openings, thus indicating that both types affect α7 kinetics. Different PAM types show different sensitivity to temperature, suggesting different mechanisms of potentiation. By using a mutant α7 receptor that is insensitive to the prototype type II PAM (PNU-120596), we show that some though not all type I PAMs share the structural determinants of potentiation. Overall, our study provides novel information on α7 potentiation, which is key to the ongoing development of therapeutic compounds. |
publishDate |
2016 |
dc.date.none.fl_str_mv |
2016-08 |
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/11336/38702 Andersen, Natalia Denise; Nielsen, Beatriz Elizabeth; Corradi, Jeremias; Tolosa, María Fernanda; Feuerbach, Dominik; et al.; Exploring the positive allosteric modulation of human α7 nicotinic receptors from a single-channel perspective; Pergamon-Elsevier Science Ltd; Neuropharmacology; 107; 8-2016; 189-200 0028-3908 CONICET Digital CONICET |
url |
http://hdl.handle.net/11336/38702 |
identifier_str_mv |
Andersen, Natalia Denise; Nielsen, Beatriz Elizabeth; Corradi, Jeremias; Tolosa, María Fernanda; Feuerbach, Dominik; et al.; Exploring the positive allosteric modulation of human α7 nicotinic receptors from a single-channel perspective; Pergamon-Elsevier Science Ltd; Neuropharmacology; 107; 8-2016; 189-200 0028-3908 CONICET Digital CONICET |
dc.language.none.fl_str_mv |
eng |
language |
eng |
dc.relation.none.fl_str_mv |
info:eu-repo/semantics/altIdentifier/url/http://www.sciencedirect.com/science/article/pii/S0028390816300673 info:eu-repo/semantics/altIdentifier/doi/10.1016/j.neuropharm.2016.02.032 |
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 application/pdf |
dc.publisher.none.fl_str_mv |
Pergamon-Elsevier Science Ltd |
publisher.none.fl_str_mv |
Pergamon-Elsevier Science Ltd |
dc.source.none.fl_str_mv |
reponame:CONICET Digital (CONICET) instname:Consejo Nacional de Investigaciones Científicas y Técnicas |
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CONICET Digital (CONICET) |
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CONICET Digital (CONICET) |
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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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1842270155049009152 |
score |
13.13397 |