Dual effect of acetylcholinesterase inhibitor on the nicotinic acetylcholine receptor

Autores
Fabiani, Camila; Corradi, Jeremias; Murray, Ana Paula; Antollini, Silvia Susana
Año de publicación
2016
Idioma
inglés
Tipo de recurso
documento de conferencia
Estado
versión publicada
Descripción
Cholinergic deficit is regarded as an important factor responsible for Alzheimer’s disease symptoms. One of the molecular targets for the treatment of this disease is acetylcholinesterase (AChE), an enzyme that hydrolyzes acetylcholine at the synaptic cleft. It has been shown that some AChE inhibitors also act at nicotinic receptors (nAChR) potentiating their therapeutic effect. We found that metabolic extracts of Camellia sinensis (red tea) exhibit a strong anticholinesterase activity. By chromatography and NMR spectroscopy we found that caffeine was the active compound exerting such effect. We next explored if caffeine has a direct effect on the nAChR. Using the AChR conformationalsensitive probe crystal violet (CrV), an AChR open channel blocker, and AChR-rich membranes from Torpedo californica, we observed that increasing concentrations of caffeine (10-300 µM) decreased the KD of CrV in the resting state without changes in the KD in the desensitized state. In the presence of α-bungarotoxin, a specific AChR competitive antagonist, a dual effect was evident: low concentrations of caffeine did not produce any effect in the KD of CrV in the resting state, whereas higher concentrations produce a great increase of this value compatible with a competition with CrV for its site on the channel pore. To confirm this, we performed single channel recordings in Bosc cells expressing the adult muscle nAChR in the presence of 30 µM ACh and increasing concentrations of caffeine (150-20000 µM). We found that the mean open duration decreases, and the relative area of the briefer closed component and the cluster duration increase as a function of caffeine concentration. All these observations are compatible with an open channel blocker. Thus, our results suggest a dual effect of caffeine on the muscle AChR: at low concentrations, in the absence of agonist, induces an AChR conformational change, whereas at high concentrations caffeine acts as an AChR open channel blocker.
Fil: Fabiani, Camila. 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: 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. Universidad Nacional del Sur. Departamento de Biología, Bioquímica y Farmacia; Argentina
Fil: Murray, Ana Paula. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Química del Sur. Universidad Nacional del Sur. Departamento de Química. Instituto de Química del Sur; Argentina
Fil: Antollini, Silvia Susana. 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
III Latin American Federation of Biophysical Societies; IX IberoAmerican Congress of Biophysics; XLV Reunion Anual Sociedad Argentina de Biofísica
Tucumán
Argentina
Sociedad Argentina de Biofísica
Materia
NICOTINIC
RECEPTORS
MODULATION
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:11336/230259
Acceder
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oai_identifier_str oai:ri.conicet.gov.ar:11336/230259
network_acronym_str CONICETDig
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network_name_str CONICET Digital (CONICET)
spelling Dual effect of acetylcholinesterase inhibitor on the nicotinic acetylcholine receptorFabiani, CamilaCorradi, JeremiasMurray, Ana PaulaAntollini, Silvia SusanaNICOTINICRECEPTORSMODULATIONhttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1Cholinergic deficit is regarded as an important factor responsible for Alzheimer’s disease symptoms. One of the molecular targets for the treatment of this disease is acetylcholinesterase (AChE), an enzyme that hydrolyzes acetylcholine at the synaptic cleft. It has been shown that some AChE inhibitors also act at nicotinic receptors (nAChR) potentiating their therapeutic effect. We found that metabolic extracts of Camellia sinensis (red tea) exhibit a strong anticholinesterase activity. By chromatography and NMR spectroscopy we found that caffeine was the active compound exerting such effect. We next explored if caffeine has a direct effect on the nAChR. Using the AChR conformationalsensitive probe crystal violet (CrV), an AChR open channel blocker, and AChR-rich membranes from Torpedo californica, we observed that increasing concentrations of caffeine (10-300 µM) decreased the KD of CrV in the resting state without changes in the KD in the desensitized state. In the presence of α-bungarotoxin, a specific AChR competitive antagonist, a dual effect was evident: low concentrations of caffeine did not produce any effect in the KD of CrV in the resting state, whereas higher concentrations produce a great increase of this value compatible with a competition with CrV for its site on the channel pore. To confirm this, we performed single channel recordings in Bosc cells expressing the adult muscle nAChR in the presence of 30 µM ACh and increasing concentrations of caffeine (150-20000 µM). We found that the mean open duration decreases, and the relative area of the briefer closed component and the cluster duration increase as a function of caffeine concentration. All these observations are compatible with an open channel blocker. Thus, our results suggest a dual effect of caffeine on the muscle AChR: at low concentrations, in the absence of agonist, induces an AChR conformational change, whereas at high concentrations caffeine acts as an AChR open channel blocker.Fil: Fabiani, Camila. 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: 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. Universidad Nacional del Sur. Departamento de Biología, Bioquímica y Farmacia; ArgentinaFil: Murray, Ana Paula. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Química del Sur. Universidad Nacional del Sur. Departamento de Química. Instituto de Química del Sur; ArgentinaFil: Antollini, Silvia Susana. 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; ArgentinaIII Latin American Federation of Biophysical Societies; IX IberoAmerican Congress of Biophysics; XLV Reunion Anual Sociedad Argentina de BiofísicaTucumánArgentinaSociedad Argentina de BiofísicaSociedad Argentina de BiofísicaSica, Mauricio Pablo2016info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/conferenceObjectCongresoBookhttp://purl.org/coar/resource_type/c_5794info:ar-repo/semantics/documentoDeConferenciaapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/230259Dual effect of acetylcholinesterase inhibitor on the nicotinic acetylcholine receptor; III Latin American Federation of Biophysical Societies; IX IberoAmerican Congress of Biophysics; XLV Reunion Anual Sociedad Argentina de Biofísica; Tucumán; Argentina; 2016; 250-251CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://biofisica.org.ar/reuniones-cientificas/reunionsab-previas/Internacionalinfo:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-03T09:47:35Zoai:ri.conicet.gov.ar:11336/230259instacron: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 09:47:35.856CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Dual effect of acetylcholinesterase inhibitor on the nicotinic acetylcholine receptor
title Dual effect of acetylcholinesterase inhibitor on the nicotinic acetylcholine receptor
spellingShingle Dual effect of acetylcholinesterase inhibitor on the nicotinic acetylcholine receptor
Fabiani, Camila
NICOTINIC
RECEPTORS
MODULATION
title_short Dual effect of acetylcholinesterase inhibitor on the nicotinic acetylcholine receptor
title_full Dual effect of acetylcholinesterase inhibitor on the nicotinic acetylcholine receptor
title_fullStr Dual effect of acetylcholinesterase inhibitor on the nicotinic acetylcholine receptor
title_full_unstemmed Dual effect of acetylcholinesterase inhibitor on the nicotinic acetylcholine receptor
title_sort Dual effect of acetylcholinesterase inhibitor on the nicotinic acetylcholine receptor
dc.creator.none.fl_str_mv Fabiani, Camila
Corradi, Jeremias
Murray, Ana Paula
Antollini, Silvia Susana
author Fabiani, Camila
author_facet Fabiani, Camila
Corradi, Jeremias
Murray, Ana Paula
Antollini, Silvia Susana
author_role author
author2 Corradi, Jeremias
Murray, Ana Paula
Antollini, Silvia Susana
author2_role author
author
author
dc.contributor.none.fl_str_mv Sica, Mauricio Pablo
dc.subject.none.fl_str_mv NICOTINIC
RECEPTORS
MODULATION
topic NICOTINIC
RECEPTORS
MODULATION
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.6
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv Cholinergic deficit is regarded as an important factor responsible for Alzheimer’s disease symptoms. One of the molecular targets for the treatment of this disease is acetylcholinesterase (AChE), an enzyme that hydrolyzes acetylcholine at the synaptic cleft. It has been shown that some AChE inhibitors also act at nicotinic receptors (nAChR) potentiating their therapeutic effect. We found that metabolic extracts of Camellia sinensis (red tea) exhibit a strong anticholinesterase activity. By chromatography and NMR spectroscopy we found that caffeine was the active compound exerting such effect. We next explored if caffeine has a direct effect on the nAChR. Using the AChR conformationalsensitive probe crystal violet (CrV), an AChR open channel blocker, and AChR-rich membranes from Torpedo californica, we observed that increasing concentrations of caffeine (10-300 µM) decreased the KD of CrV in the resting state without changes in the KD in the desensitized state. In the presence of α-bungarotoxin, a specific AChR competitive antagonist, a dual effect was evident: low concentrations of caffeine did not produce any effect in the KD of CrV in the resting state, whereas higher concentrations produce a great increase of this value compatible with a competition with CrV for its site on the channel pore. To confirm this, we performed single channel recordings in Bosc cells expressing the adult muscle nAChR in the presence of 30 µM ACh and increasing concentrations of caffeine (150-20000 µM). We found that the mean open duration decreases, and the relative area of the briefer closed component and the cluster duration increase as a function of caffeine concentration. All these observations are compatible with an open channel blocker. Thus, our results suggest a dual effect of caffeine on the muscle AChR: at low concentrations, in the absence of agonist, induces an AChR conformational change, whereas at high concentrations caffeine acts as an AChR open channel blocker.
Fil: Fabiani, Camila. 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: 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. Universidad Nacional del Sur. Departamento de Biología, Bioquímica y Farmacia; Argentina
Fil: Murray, Ana Paula. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Química del Sur. Universidad Nacional del Sur. Departamento de Química. Instituto de Química del Sur; Argentina
Fil: Antollini, Silvia Susana. 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
III Latin American Federation of Biophysical Societies; IX IberoAmerican Congress of Biophysics; XLV Reunion Anual Sociedad Argentina de Biofísica
Tucumán
Argentina
Sociedad Argentina de Biofísica
description Cholinergic deficit is regarded as an important factor responsible for Alzheimer’s disease symptoms. One of the molecular targets for the treatment of this disease is acetylcholinesterase (AChE), an enzyme that hydrolyzes acetylcholine at the synaptic cleft. It has been shown that some AChE inhibitors also act at nicotinic receptors (nAChR) potentiating their therapeutic effect. We found that metabolic extracts of Camellia sinensis (red tea) exhibit a strong anticholinesterase activity. By chromatography and NMR spectroscopy we found that caffeine was the active compound exerting such effect. We next explored if caffeine has a direct effect on the nAChR. Using the AChR conformationalsensitive probe crystal violet (CrV), an AChR open channel blocker, and AChR-rich membranes from Torpedo californica, we observed that increasing concentrations of caffeine (10-300 µM) decreased the KD of CrV in the resting state without changes in the KD in the desensitized state. In the presence of α-bungarotoxin, a specific AChR competitive antagonist, a dual effect was evident: low concentrations of caffeine did not produce any effect in the KD of CrV in the resting state, whereas higher concentrations produce a great increase of this value compatible with a competition with CrV for its site on the channel pore. To confirm this, we performed single channel recordings in Bosc cells expressing the adult muscle nAChR in the presence of 30 µM ACh and increasing concentrations of caffeine (150-20000 µM). We found that the mean open duration decreases, and the relative area of the briefer closed component and the cluster duration increase as a function of caffeine concentration. All these observations are compatible with an open channel blocker. Thus, our results suggest a dual effect of caffeine on the muscle AChR: at low concentrations, in the absence of agonist, induces an AChR conformational change, whereas at high concentrations caffeine acts as an AChR open channel blocker.
publishDate 2016
dc.date.none.fl_str_mv 2016
dc.type.none.fl_str_mv info:eu-repo/semantics/publishedVersion
info:eu-repo/semantics/conferenceObject
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Book
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/11336/230259
Dual effect of acetylcholinesterase inhibitor on the nicotinic acetylcholine receptor; III Latin American Federation of Biophysical Societies; IX IberoAmerican Congress of Biophysics; XLV Reunion Anual Sociedad Argentina de Biofísica; Tucumán; Argentina; 2016; 250-251
CONICET Digital
CONICET
url http://hdl.handle.net/11336/230259
identifier_str_mv Dual effect of acetylcholinesterase inhibitor on the nicotinic acetylcholine receptor; III Latin American Federation of Biophysical Societies; IX IberoAmerican Congress of Biophysics; XLV Reunion Anual Sociedad Argentina de Biofísica; Tucumán; Argentina; 2016; 250-251
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://biofisica.org.ar/reuniones-cientificas/reunionsab-previas/
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
eu_rights_str_mv openAccess
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.coverage.none.fl_str_mv Internacional
dc.publisher.none.fl_str_mv Sociedad Argentina de Biofísica
publisher.none.fl_str_mv Sociedad Argentina de Biofísica
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
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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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