Flavonoids as allosteric modulators of alpha7 nicotinic receptor

Autores
Nielsen, Beatriz Elizabeth; Bouzat, Cecilia Beatriz
Año de publicación
2017
Idioma
inglés
Tipo de recurso
documento de conferencia
Estado
versión publicada
Descripción
Ubiquitously present in plants, flavonoids are a class of polyphe- nolic compounds comprising a benzopyrone moiety. These com- pounds have been reported to decline incidence rate and develop- ment of several neurodegenerative disorders, such as Alzheimer’s and Parkinson’s diseases. Two flavonoids, genistein and quercetin, have been also described as type I positive allosteric modulators (PAMs) of α7 nicotinic acetylcholine receptor, which increase the amplitude of macroscopic responses evoked by ACh without chan- ging the desensitization rate. The molecular mechanism underlying these macroscopic effects remains unknown. Our main objective is to unravel the molecular basis of flavonoid allosteric potentiation of α7 at the single-channel level. Receptors were expressed in mam- malian cells and receptor function was evaluated by patch-clamp recordings. We analyzed the concentration-dependent effects of a prototype flavonoid for each class: quercetin as flavones, genistein as isoflavones and 5,7-dihydroxy-4-phenylcoumarin as neoflavo- noids. We here reported for the first time that neoflavonoids act as PAMs of α7. All flavonoids increased the mean open channel lifetime and the mean burst duration of α7, although the magnitude of the change differed among the different compounds. In order to define the structural and functional determinants of potentiation, we eva- luated flavonoid potentiation in an α7 receptor carrying a quintuple mutation at the transmembrane region that makes it insensitive to potentiation by type II PAMs and in a chimeric α7-5HT3 A receptor with the extracellular domain of α7 and the transmembrane region of 5-HT3 A. Statistically significance differences were established at p-values<0.05. We conclude that, in addition to the well-known effects as antioxidants, the unique properties of flavonoids as natu- ral α7 PAMs make them candidate drugs for the treatment of diffe- rent neurodegenerative disorders
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. 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
LXII Reunión Anual de la Sociedad Argentina de Investigación Clínica; LII Reunión Anual de la Sociedad Argentina de Investigación Bioquímica y Biología Molecular; LXV Reunión Anual de la Sociedad Argentina de Inmunología; Reunión de la Sociedad Argentina de Andrología; XLVI Reunión Anual de la Sociedad Argentina de Biofísica; XIX Reunión Anual de la Sociedad Argentina de Biología; XLIX Reunión Anual de la Sociedad Argentina de Farmacología Experimental; Reunión Anual de la Sociedad Argentina de Fisiología; Reunión de la Sociedad Argentina de Hematología y XXIX Reunión Anual de la Sociedad Argentina de Protozoología
Buenos Aires
Argentina
Sociedad Argentina de Investigación Clínica
Sociedad Argentina de Investigación Bioquímica y Biología Molecular
Sociedad Argentina de Inmunología
Sociedad Argentina de Andrología
Sociedad Argentina de Biofísica
Sociedad Argentina de Biología
Sociedad Argentina de Farmacología Experimental
Sociedad Argentina de Fisiologia
Sociedad Argentina de Hematología
Sociedad Argentina de Protozoología
Materia
alpha 7 nicotinic receptor
flavonoids
positive allosteric modulators
patch-clamp
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:11336/234115
Acceder
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network_name_str CONICET Digital (CONICET)
spelling Flavonoids as allosteric modulators of alpha7 nicotinic receptorNielsen, Beatriz ElizabethBouzat, Cecilia Beatrizalpha 7 nicotinic receptorflavonoidspositive allosteric modulatorspatch-clamphttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1Ubiquitously present in plants, flavonoids are a class of polyphe- nolic compounds comprising a benzopyrone moiety. These com- pounds have been reported to decline incidence rate and develop- ment of several neurodegenerative disorders, such as Alzheimer’s and Parkinson’s diseases. Two flavonoids, genistein and quercetin, have been also described as type I positive allosteric modulators (PAMs) of α7 nicotinic acetylcholine receptor, which increase the amplitude of macroscopic responses evoked by ACh without chan- ging the desensitization rate. The molecular mechanism underlying these macroscopic effects remains unknown. Our main objective is to unravel the molecular basis of flavonoid allosteric potentiation of α7 at the single-channel level. Receptors were expressed in mam- malian cells and receptor function was evaluated by patch-clamp recordings. We analyzed the concentration-dependent effects of a prototype flavonoid for each class: quercetin as flavones, genistein as isoflavones and 5,7-dihydroxy-4-phenylcoumarin as neoflavo- noids. We here reported for the first time that neoflavonoids act as PAMs of α7. All flavonoids increased the mean open channel lifetime and the mean burst duration of α7, although the magnitude of the change differed among the different compounds. In order to define the structural and functional determinants of potentiation, we eva- luated flavonoid potentiation in an α7 receptor carrying a quintuple mutation at the transmembrane region that makes it insensitive to potentiation by type II PAMs and in a chimeric α7-5HT3 A receptor with the extracellular domain of α7 and the transmembrane region of 5-HT3 A. Statistically significance differences were established at p-values<0.05. We conclude that, in addition to the well-known effects as antioxidants, the unique properties of flavonoids as natu- ral α7 PAMs make them candidate drugs for the treatment of diffe- rent neurodegenerative disordersFil: 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. 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; ArgentinaLXII Reunión Anual de la Sociedad Argentina de Investigación Clínica; LII Reunión Anual de la Sociedad Argentina de Investigación Bioquímica y Biología Molecular; LXV Reunión Anual de la Sociedad Argentina de Inmunología; Reunión de la Sociedad Argentina de Andrología; XLVI Reunión Anual de la Sociedad Argentina de Biofísica; XIX Reunión Anual de la Sociedad Argentina de Biología; XLIX Reunión Anual de la Sociedad Argentina de Farmacología Experimental; Reunión Anual de la Sociedad Argentina de Fisiología; Reunión de la Sociedad Argentina de Hematología y XXIX Reunión Anual de la Sociedad Argentina de ProtozoologíaBuenos AiresArgentinaSociedad Argentina de Investigación ClínicaSociedad Argentina de Investigación Bioquímica y Biología MolecularSociedad Argentina de InmunologíaSociedad Argentina de AndrologíaSociedad Argentina de BiofísicaSociedad Argentina de BiologíaSociedad Argentina de Farmacología ExperimentalSociedad Argentina de FisiologiaSociedad Argentina de HematologíaSociedad Argentina de ProtozoologíaFundación Revista Medicina2017info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/conferenceObjectReuniónJournalhttp://purl.org/coar/resource_type/c_5794info:ar-repo/semantics/documentoDeConferenciaapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/234115Flavonoids as allosteric modulators of alpha7 nicotinic receptor; LXII Reunión Anual de la Sociedad Argentina de Investigación Clínica; LII Reunión Anual de la Sociedad Argentina de Investigación Bioquímica y Biología Molecular; LXV Reunión Anual de la Sociedad Argentina de Inmunología; Reunión de la Sociedad Argentina de Andrología; XLVI Reunión Anual de la Sociedad Argentina de Biofísica; XIX Reunión Anual de la Sociedad Argentina de Biología; XLIX Reunión Anual de la Sociedad Argentina de Farmacología Experimental; Reunión Anual de la Sociedad Argentina de Fisiología; Reunión de la Sociedad Argentina de Hematología y XXIX Reunión Anual de la Sociedad Argentina de Protozoología; Buenos Aires; Argentina; 2017; 506-5070025-76801669-9106CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://www.saic.org.ar/revista-medicinaNacionalinfo:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-03T10:09:19Zoai:ri.conicet.gov.ar:11336/234115instacron: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 10:09:19.559CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Flavonoids as allosteric modulators of alpha7 nicotinic receptor
title Flavonoids as allosteric modulators of alpha7 nicotinic receptor
spellingShingle Flavonoids as allosteric modulators of alpha7 nicotinic receptor
Nielsen, Beatriz Elizabeth
alpha 7 nicotinic receptor
flavonoids
positive allosteric modulators
patch-clamp
title_short Flavonoids as allosteric modulators of alpha7 nicotinic receptor
title_full Flavonoids as allosteric modulators of alpha7 nicotinic receptor
title_fullStr Flavonoids as allosteric modulators of alpha7 nicotinic receptor
title_full_unstemmed Flavonoids as allosteric modulators of alpha7 nicotinic receptor
title_sort Flavonoids as allosteric modulators of alpha7 nicotinic receptor
dc.creator.none.fl_str_mv Nielsen, Beatriz Elizabeth
Bouzat, Cecilia Beatriz
author Nielsen, Beatriz Elizabeth
author_facet Nielsen, Beatriz Elizabeth
Bouzat, Cecilia Beatriz
author_role author
author2 Bouzat, Cecilia Beatriz
author2_role author
dc.subject.none.fl_str_mv alpha 7 nicotinic receptor
flavonoids
positive allosteric modulators
patch-clamp
topic alpha 7 nicotinic receptor
flavonoids
positive allosteric modulators
patch-clamp
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.6
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv Ubiquitously present in plants, flavonoids are a class of polyphe- nolic compounds comprising a benzopyrone moiety. These com- pounds have been reported to decline incidence rate and develop- ment of several neurodegenerative disorders, such as Alzheimer’s and Parkinson’s diseases. Two flavonoids, genistein and quercetin, have been also described as type I positive allosteric modulators (PAMs) of α7 nicotinic acetylcholine receptor, which increase the amplitude of macroscopic responses evoked by ACh without chan- ging the desensitization rate. The molecular mechanism underlying these macroscopic effects remains unknown. Our main objective is to unravel the molecular basis of flavonoid allosteric potentiation of α7 at the single-channel level. Receptors were expressed in mam- malian cells and receptor function was evaluated by patch-clamp recordings. We analyzed the concentration-dependent effects of a prototype flavonoid for each class: quercetin as flavones, genistein as isoflavones and 5,7-dihydroxy-4-phenylcoumarin as neoflavo- noids. We here reported for the first time that neoflavonoids act as PAMs of α7. All flavonoids increased the mean open channel lifetime and the mean burst duration of α7, although the magnitude of the change differed among the different compounds. In order to define the structural and functional determinants of potentiation, we eva- luated flavonoid potentiation in an α7 receptor carrying a quintuple mutation at the transmembrane region that makes it insensitive to potentiation by type II PAMs and in a chimeric α7-5HT3 A receptor with the extracellular domain of α7 and the transmembrane region of 5-HT3 A. Statistically significance differences were established at p-values<0.05. We conclude that, in addition to the well-known effects as antioxidants, the unique properties of flavonoids as natu- ral α7 PAMs make them candidate drugs for the treatment of diffe- rent neurodegenerative disorders
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. 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
LXII Reunión Anual de la Sociedad Argentina de Investigación Clínica; LII Reunión Anual de la Sociedad Argentina de Investigación Bioquímica y Biología Molecular; LXV Reunión Anual de la Sociedad Argentina de Inmunología; Reunión de la Sociedad Argentina de Andrología; XLVI Reunión Anual de la Sociedad Argentina de Biofísica; XIX Reunión Anual de la Sociedad Argentina de Biología; XLIX Reunión Anual de la Sociedad Argentina de Farmacología Experimental; Reunión Anual de la Sociedad Argentina de Fisiología; Reunión de la Sociedad Argentina de Hematología y XXIX Reunión Anual de la Sociedad Argentina de Protozoología
Buenos Aires
Argentina
Sociedad Argentina de Investigación Clínica
Sociedad Argentina de Investigación Bioquímica y Biología Molecular
Sociedad Argentina de Inmunología
Sociedad Argentina de Andrología
Sociedad Argentina de Biofísica
Sociedad Argentina de Biología
Sociedad Argentina de Farmacología Experimental
Sociedad Argentina de Fisiologia
Sociedad Argentina de Hematología
Sociedad Argentina de Protozoología
description Ubiquitously present in plants, flavonoids are a class of polyphe- nolic compounds comprising a benzopyrone moiety. These com- pounds have been reported to decline incidence rate and develop- ment of several neurodegenerative disorders, such as Alzheimer’s and Parkinson’s diseases. Two flavonoids, genistein and quercetin, have been also described as type I positive allosteric modulators (PAMs) of α7 nicotinic acetylcholine receptor, which increase the amplitude of macroscopic responses evoked by ACh without chan- ging the desensitization rate. The molecular mechanism underlying these macroscopic effects remains unknown. Our main objective is to unravel the molecular basis of flavonoid allosteric potentiation of α7 at the single-channel level. Receptors were expressed in mam- malian cells and receptor function was evaluated by patch-clamp recordings. We analyzed the concentration-dependent effects of a prototype flavonoid for each class: quercetin as flavones, genistein as isoflavones and 5,7-dihydroxy-4-phenylcoumarin as neoflavo- noids. We here reported for the first time that neoflavonoids act as PAMs of α7. All flavonoids increased the mean open channel lifetime and the mean burst duration of α7, although the magnitude of the change differed among the different compounds. In order to define the structural and functional determinants of potentiation, we eva- luated flavonoid potentiation in an α7 receptor carrying a quintuple mutation at the transmembrane region that makes it insensitive to potentiation by type II PAMs and in a chimeric α7-5HT3 A receptor with the extracellular domain of α7 and the transmembrane region of 5-HT3 A. Statistically significance differences were established at p-values<0.05. We conclude that, in addition to the well-known effects as antioxidants, the unique properties of flavonoids as natu- ral α7 PAMs make them candidate drugs for the treatment of diffe- rent neurodegenerative disorders
publishDate 2017
dc.date.none.fl_str_mv 2017
dc.type.none.fl_str_mv info:eu-repo/semantics/publishedVersion
info:eu-repo/semantics/conferenceObject
Reunión
Journal
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/11336/234115
Flavonoids as allosteric modulators of alpha7 nicotinic receptor; LXII Reunión Anual de la Sociedad Argentina de Investigación Clínica; LII Reunión Anual de la Sociedad Argentina de Investigación Bioquímica y Biología Molecular; LXV Reunión Anual de la Sociedad Argentina de Inmunología; Reunión de la Sociedad Argentina de Andrología; XLVI Reunión Anual de la Sociedad Argentina de Biofísica; XIX Reunión Anual de la Sociedad Argentina de Biología; XLIX Reunión Anual de la Sociedad Argentina de Farmacología Experimental; Reunión Anual de la Sociedad Argentina de Fisiología; Reunión de la Sociedad Argentina de Hematología y XXIX Reunión Anual de la Sociedad Argentina de Protozoología; Buenos Aires; Argentina; 2017; 506-507
0025-7680
1669-9106
CONICET Digital
CONICET
url http://hdl.handle.net/11336/234115
identifier_str_mv Flavonoids as allosteric modulators of alpha7 nicotinic receptor; LXII Reunión Anual de la Sociedad Argentina de Investigación Clínica; LII Reunión Anual de la Sociedad Argentina de Investigación Bioquímica y Biología Molecular; LXV Reunión Anual de la Sociedad Argentina de Inmunología; Reunión de la Sociedad Argentina de Andrología; XLVI Reunión Anual de la Sociedad Argentina de Biofísica; XIX Reunión Anual de la Sociedad Argentina de Biología; XLIX Reunión Anual de la Sociedad Argentina de Farmacología Experimental; Reunión Anual de la Sociedad Argentina de Fisiología; Reunión de la Sociedad Argentina de Hematología y XXIX Reunión Anual de la Sociedad Argentina de Protozoología; Buenos Aires; Argentina; 2017; 506-507
0025-7680
1669-9106
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
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eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
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application/pdf
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dc.coverage.none.fl_str_mv Nacional
dc.publisher.none.fl_str_mv Fundación Revista Medicina
publisher.none.fl_str_mv Fundación Revista Medicina
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str CONICET Digital (CONICET)
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instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
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repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
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