Single-channel and structural foundations of neuronal alpha7 acetylcholine receptor potentiation

Autores
daCosta, Corrie J. B.; Free, Chris R.; Corradi, Jeremias; Bouzat, Cecilia Beatriz; Sine, Steven M.
Año de publicación
2011
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Potentiation of neuronal nicotinic acetylcholine receptors by exogenous ligands is a promising strategy for treatment of neurological disorders including Alzheimer´s disease and schizophrenia. To gain insight into molecular mechanisms underlying potentiation, we examined ACh-induced single-channel currents through the human neuronal alpha7 acetylcholine receptor in the presence of the alpha7-specific potentiator PNU-120596 (PNU). Compared to the unusually brief single-channel opening episodes elicited by agonist alone, channel opening episodes in the presence of agonist and PNU are dramatically prolonged. Dwell time analysis reveals that PNU introduces two
novel components into open time histograms, indicating at least two degrees of PNU-induced potentiation. Openings of the longest potentiated class coalesce into clusters whose frequency and duration change over a narrow range of PNU concentration. At PNU concentrations approaching saturation, these clusters last up to several minutes, prolonging the submillisecond alpha7 opening episodes by several orders of magnitude. Mutations known to reduce PNU potentiation at the whole-cell level still give rise to multisecond-long single-channel clusters. However mutation of five residues lining a cavity within each subunit´s transmembrane domain abolishes PNU potentiation, defining minimal structural determinants of PNU potentiation. 
Fil: daCosta, Corrie J. B.. Mayo Clinic College of Medicine; Estados Unidos
Fil: Free, Chris R.. Mayo Clinic College of Medicine; Estados Unidos
Fil: Corradi, Jeremias. Consejo Nacional de Investigaciones Cientificas y Técnicas. Centro Científico Tecnológico Bahia Blanca. Instituto de Investigaciones Bioquímicas Bahia Blanca (i); Argentina. Universidad Nacional del Sur; Argentina
Fil: Bouzat, Cecilia Beatriz. Consejo Nacional de Investigaciones Cientificas y Técnicas. Centro Científico Tecnológico Bahia Blanca. Instituto de Investigaciones Bioquímicas Bahia Blanca (i); Argentina. Universidad Nacional del Sur; Argentina
Fil: Sine, Steven M.. Mayo Clinic College of Medicine; Estados Unidos
Materia
RECEPTORS
MODULATORS
POTENTIATION
DESENSITIZATION
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/6466
Acceder
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network_name_str CONICET Digital (CONICET)
spelling Single-channel and structural foundations of neuronal alpha7 acetylcholine receptor potentiationdaCosta, Corrie J. B.Free, Chris R.Corradi, JeremiasBouzat, Cecilia BeatrizSine, Steven M.RECEPTORSMODULATORSPOTENTIATIONDESENSITIZATIONhttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1Potentiation of neuronal nicotinic acetylcholine receptors by exogenous ligands is a promising strategy for treatment of neurological disorders including Alzheimer´s disease and schizophrenia. To gain insight into molecular mechanisms underlying potentiation, we examined ACh-induced single-channel currents through the human neuronal alpha7 acetylcholine receptor in the presence of the alpha7-specific potentiator PNU-120596 (PNU). Compared to the unusually brief single-channel opening episodes elicited by agonist alone, channel opening episodes in the presence of agonist and PNU are dramatically prolonged. Dwell time analysis reveals that PNU introduces two <br />novel components into open time histograms, indicating at least two degrees of PNU-induced potentiation. Openings of the longest potentiated class coalesce into clusters whose frequency and duration change over a narrow range of PNU concentration. At PNU concentrations approaching saturation, these clusters last up to several minutes, prolonging the submillisecond alpha7 opening episodes by several orders of magnitude. Mutations known to reduce PNU potentiation at the whole-cell level still give rise to multisecond-long single-channel clusters. However mutation of five residues lining a cavity within each subunit´s transmembrane domain abolishes PNU potentiation, defining minimal structural determinants of PNU potentiation. Fil: daCosta, Corrie J. B.. Mayo Clinic College of Medicine; Estados UnidosFil: Free, Chris R.. Mayo Clinic College of Medicine; Estados UnidosFil: Corradi, Jeremias. Consejo Nacional de Investigaciones Cientificas y Técnicas. Centro Científico Tecnológico Bahia Blanca. Instituto de Investigaciones Bioquímicas Bahia Blanca (i); Argentina. Universidad Nacional del Sur; ArgentinaFil: Bouzat, Cecilia Beatriz. Consejo Nacional de Investigaciones Cientificas y Técnicas. Centro Científico Tecnológico Bahia Blanca. Instituto de Investigaciones Bioquímicas Bahia Blanca (i); Argentina. Universidad Nacional del Sur; ArgentinaFil: Sine, Steven M.. Mayo Clinic College of Medicine; Estados UnidosSociety for Neuroscience2011-09info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/6466daCosta, Corrie J. B.; Free, Chris R.; Corradi, Jeremias; Bouzat, Cecilia Beatriz; Sine, Steven M.; Single-channel and structural foundations of neuronal alpha7 acetylcholine receptor potentiation; Society for Neuroscience; Journal of Neuroscience; 31; 39; 9-2011; 13870-138790270-6474enginfo:eu-repo/semantics/altIdentifier/doi/10.1523/JNEUROSCI.2652-11.2011info:eu-repo/semantics/altIdentifier/doi/info:eu-repo/semantics/altIdentifier/pmid/PMC3226716info:eu-repo/semantics/altIdentifier/url/http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3226716/info:eu-repo/semantics/altIdentifier/url/http://www.jneurosci.org/content/31/39/13870info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2026-04-15T10:55:07Zoai:ri.conicet.gov.ar:11336/6466instacron: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:34982026-04-15 10:55:08.156CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Single-channel and structural foundations of neuronal alpha7 acetylcholine receptor potentiation
title Single-channel and structural foundations of neuronal alpha7 acetylcholine receptor potentiation
spellingShingle Single-channel and structural foundations of neuronal alpha7 acetylcholine receptor potentiation
daCosta, Corrie J. B.
RECEPTORS
MODULATORS
POTENTIATION
DESENSITIZATION
title_short Single-channel and structural foundations of neuronal alpha7 acetylcholine receptor potentiation
title_full Single-channel and structural foundations of neuronal alpha7 acetylcholine receptor potentiation
title_fullStr Single-channel and structural foundations of neuronal alpha7 acetylcholine receptor potentiation
title_full_unstemmed Single-channel and structural foundations of neuronal alpha7 acetylcholine receptor potentiation
title_sort Single-channel and structural foundations of neuronal alpha7 acetylcholine receptor potentiation
dc.creator.none.fl_str_mv daCosta, Corrie J. B.
Free, Chris R.
Corradi, Jeremias
Bouzat, Cecilia Beatriz
Sine, Steven M.
author daCosta, Corrie J. B.
author_facet daCosta, Corrie J. B.
Free, Chris R.
Corradi, Jeremias
Bouzat, Cecilia Beatriz
Sine, Steven M.
author_role author
author2 Free, Chris R.
Corradi, Jeremias
Bouzat, Cecilia Beatriz
Sine, Steven M.
author2_role author
author
author
author
dc.subject.none.fl_str_mv RECEPTORS
MODULATORS
POTENTIATION
DESENSITIZATION
topic RECEPTORS
MODULATORS
POTENTIATION
DESENSITIZATION
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.6
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv Potentiation of neuronal nicotinic acetylcholine receptors by exogenous ligands is a promising strategy for treatment of neurological disorders including Alzheimer´s disease and schizophrenia. To gain insight into molecular mechanisms underlying potentiation, we examined ACh-induced single-channel currents through the human neuronal alpha7 acetylcholine receptor in the presence of the alpha7-specific potentiator PNU-120596 (PNU). Compared to the unusually brief single-channel opening episodes elicited by agonist alone, channel opening episodes in the presence of agonist and PNU are dramatically prolonged. Dwell time analysis reveals that PNU introduces two <br />novel components into open time histograms, indicating at least two degrees of PNU-induced potentiation. Openings of the longest potentiated class coalesce into clusters whose frequency and duration change over a narrow range of PNU concentration. At PNU concentrations approaching saturation, these clusters last up to several minutes, prolonging the submillisecond alpha7 opening episodes by several orders of magnitude. Mutations known to reduce PNU potentiation at the whole-cell level still give rise to multisecond-long single-channel clusters. However mutation of five residues lining a cavity within each subunit´s transmembrane domain abolishes PNU potentiation, defining minimal structural determinants of PNU potentiation. 
Fil: daCosta, Corrie J. B.. Mayo Clinic College of Medicine; Estados Unidos
Fil: Free, Chris R.. Mayo Clinic College of Medicine; Estados Unidos
Fil: Corradi, Jeremias. Consejo Nacional de Investigaciones Cientificas y Técnicas. Centro Científico Tecnológico Bahia Blanca. Instituto de Investigaciones Bioquímicas Bahia Blanca (i); Argentina. Universidad Nacional del Sur; Argentina
Fil: Bouzat, Cecilia Beatriz. Consejo Nacional de Investigaciones Cientificas y Técnicas. Centro Científico Tecnológico Bahia Blanca. Instituto de Investigaciones Bioquímicas Bahia Blanca (i); Argentina. Universidad Nacional del Sur; Argentina
Fil: Sine, Steven M.. Mayo Clinic College of Medicine; Estados Unidos
description Potentiation of neuronal nicotinic acetylcholine receptors by exogenous ligands is a promising strategy for treatment of neurological disorders including Alzheimer´s disease and schizophrenia. To gain insight into molecular mechanisms underlying potentiation, we examined ACh-induced single-channel currents through the human neuronal alpha7 acetylcholine receptor in the presence of the alpha7-specific potentiator PNU-120596 (PNU). Compared to the unusually brief single-channel opening episodes elicited by agonist alone, channel opening episodes in the presence of agonist and PNU are dramatically prolonged. Dwell time analysis reveals that PNU introduces two <br />novel components into open time histograms, indicating at least two degrees of PNU-induced potentiation. Openings of the longest potentiated class coalesce into clusters whose frequency and duration change over a narrow range of PNU concentration. At PNU concentrations approaching saturation, these clusters last up to several minutes, prolonging the submillisecond alpha7 opening episodes by several orders of magnitude. Mutations known to reduce PNU potentiation at the whole-cell level still give rise to multisecond-long single-channel clusters. However mutation of five residues lining a cavity within each subunit´s transmembrane domain abolishes PNU potentiation, defining minimal structural determinants of PNU potentiation. 
publishDate 2011
dc.date.none.fl_str_mv 2011-09
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/11336/6466
daCosta, Corrie J. B.; Free, Chris R.; Corradi, Jeremias; Bouzat, Cecilia Beatriz; Sine, Steven M.; Single-channel and structural foundations of neuronal alpha7 acetylcholine receptor potentiation; Society for Neuroscience; Journal of Neuroscience; 31; 39; 9-2011; 13870-13879
0270-6474
url http://hdl.handle.net/11336/6466
identifier_str_mv daCosta, Corrie J. B.; Free, Chris R.; Corradi, Jeremias; Bouzat, Cecilia Beatriz; Sine, Steven M.; Single-channel and structural foundations of neuronal alpha7 acetylcholine receptor potentiation; Society for Neuroscience; Journal of Neuroscience; 31; 39; 9-2011; 13870-13879
0270-6474
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/doi/10.1523/JNEUROSCI.2652-11.2011
info:eu-repo/semantics/altIdentifier/doi/
info:eu-repo/semantics/altIdentifier/pmid/PMC3226716
info:eu-repo/semantics/altIdentifier/url/http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3226716/
info:eu-repo/semantics/altIdentifier/url/http://www.jneurosci.org/content/31/39/13870
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv Society for Neuroscience
publisher.none.fl_str_mv Society for Neuroscience
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 13.203462

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