Positive modulation of the a9a10 nicotinic cholinergic receptor by ascorbic acid

Autores
Boffi, Juan Carlos; Wedemeyer, Carolina; Lipovsek, Maria Marcela; Katz, Eleonora; Calvo, Daniel Juan; Elgoyhen, Ana Belen
Año de publicación
2013
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Background and Purpose: The activation of α9α10 nicotinic cholinergic receptors (nAChRs) present at the synapse between efferent olivocochlear fibres and cochlear hair cells can prevent acoustic trauma. Hence, pharmacological potentiators of these receptors could be useful therapeutically. In this work, we characterize ascorbic acid as a positive modulator of recombinant α9α10 nAChRs. Experimental Approach: ACh-evoked responses were analysed under two-electrode voltage-clamp recordings in Xenopus laevis oocytes injected with α9 and α10 cRNAs. Key Results: Ascorbic acid potentiated ACh responses in X. laevis oocytes expressing α9α10 (but not α4β2 or α7) nAChRs, in a concentration-dependent manner, with an effective concentration range of 1–30 mM. The compound did not affect the receptor's current–voltage profile nor its apparent affinity for ACh, but it significantly enhanced the maximal evoked currents (percentage of ACh maximal response, 240 ± 20%). This effect was specific for the L form of reduced ascorbic acid. Substitution of the extracellular cysteine residues present in loop C of the ACh binding site did not affect the potentiation. Ascorbic acid turned into a partial agonist of α9α10 nAChRs bearing a point mutation at the pore domain of the channel (TM2 V13′T mutant). A positive allosteric mechanism of action rather than an antioxidant effect of ascorbic acid is proposed. Conclusions and Implications: The present work describes one of the few agents that activates or potentiates α9α10 nAChRs and leads to new avenues for designing drugs with potential therapeutic use in inner ear disorders.
Fil: Boffi, Juan Carlos. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular; Argentina
Fil: Wedemeyer, Carolina. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular; Argentina
Fil: Lipovsek, Maria Marcela. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular; Argentina
Fil: Katz, Eleonora. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular; Argentina
Fil: Calvo, Daniel Juan. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular; Argentina
Fil: Elgoyhen, Ana Belen. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Farmacología; Argentina
Materia
Ascorbic Acid
Nicotinic Receptors
Pams
Alpha9alpha10
Ascorbate
Vitamin C
Positive Allosteric Modulator
Redox Modulator
Efferent Olivocochlear
Acoustic Trauma
Hearing Loss
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:11336/4012
Acceder
id CONICETDig_7aaa12945deb13186a33c5401927cdfe
oai_identifier_str oai:ri.conicet.gov.ar:11336/4012
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Positive modulation of the a9a10 nicotinic cholinergic receptor by ascorbic acidBoffi, Juan CarlosWedemeyer, CarolinaLipovsek, Maria MarcelaKatz, EleonoraCalvo, Daniel JuanElgoyhen, Ana BelenAscorbic AcidNicotinic ReceptorsPamsAlpha9alpha10AscorbateVitamin CPositive Allosteric ModulatorRedox ModulatorEfferent OlivocochlearAcoustic TraumaHearing Losshttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1Background and Purpose: The activation of α9α10 nicotinic cholinergic receptors (nAChRs) present at the synapse between efferent olivocochlear fibres and cochlear hair cells can prevent acoustic trauma. Hence, pharmacological potentiators of these receptors could be useful therapeutically. In this work, we characterize ascorbic acid as a positive modulator of recombinant α9α10 nAChRs. Experimental Approach: ACh-evoked responses were analysed under two-electrode voltage-clamp recordings in Xenopus laevis oocytes injected with α9 and α10 cRNAs. Key Results: Ascorbic acid potentiated ACh responses in X. laevis oocytes expressing α9α10 (but not α4β2 or α7) nAChRs, in a concentration-dependent manner, with an effective concentration range of 1–30 mM. The compound did not affect the receptor's current–voltage profile nor its apparent affinity for ACh, but it significantly enhanced the maximal evoked currents (percentage of ACh maximal response, 240 ± 20%). This effect was specific for the L form of reduced ascorbic acid. Substitution of the extracellular cysteine residues present in loop C of the ACh binding site did not affect the potentiation. Ascorbic acid turned into a partial agonist of α9α10 nAChRs bearing a point mutation at the pore domain of the channel (TM2 V13′T mutant). A positive allosteric mechanism of action rather than an antioxidant effect of ascorbic acid is proposed. Conclusions and Implications: The present work describes one of the few agents that activates or potentiates α9α10 nAChRs and leads to new avenues for designing drugs with potential therapeutic use in inner ear disorders.Fil: Boffi, Juan Carlos. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular; ArgentinaFil: Wedemeyer, Carolina. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular; ArgentinaFil: Lipovsek, Maria Marcela. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular; ArgentinaFil: Katz, Eleonora. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular; ArgentinaFil: Calvo, Daniel Juan. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular; ArgentinaFil: Elgoyhen, Ana Belen. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Farmacología; ArgentinaWiley2013-01-24info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/4012Boffi, Juan Carlos; Wedemeyer, Carolina; Lipovsek, Maria Marcela; Katz, Eleonora; Calvo, Daniel Juan; et al.; Positive modulation of the a9a10 nicotinic cholinergic receptor by ascorbic acid; Wiley; British Journal of Pharmacology; 168; 4; 24-1-2013; 954-9651476-5381enginfo:eu-repo/semantics/altIdentifier/url/http://onlinelibrary.wiley.com/doi/10.1111/j.1476-5381.2012.02221.x/abstractinfo:eu-repo/semantics/altIdentifier/issn/1476-5381info:eu-repo/semantics/altIdentifier/doi/DOI:10.1111/j.1476-5381.2012.02221.xinfo:eu-repo/semantics/altIdentifier/url/http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3631383/info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-17T11:23:39Zoai:ri.conicet.gov.ar:11336/4012instacron: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:34982025-09-17 11:23:39.834CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Positive modulation of the a9a10 nicotinic cholinergic receptor by ascorbic acid
title Positive modulation of the a9a10 nicotinic cholinergic receptor by ascorbic acid
spellingShingle Positive modulation of the a9a10 nicotinic cholinergic receptor by ascorbic acid
Boffi, Juan Carlos
Ascorbic Acid
Nicotinic Receptors
Pams
Alpha9alpha10
Ascorbate
Vitamin C
Positive Allosteric Modulator
Redox Modulator
Efferent Olivocochlear
Acoustic Trauma
Hearing Loss
title_short Positive modulation of the a9a10 nicotinic cholinergic receptor by ascorbic acid
title_full Positive modulation of the a9a10 nicotinic cholinergic receptor by ascorbic acid
title_fullStr Positive modulation of the a9a10 nicotinic cholinergic receptor by ascorbic acid
title_full_unstemmed Positive modulation of the a9a10 nicotinic cholinergic receptor by ascorbic acid
title_sort Positive modulation of the a9a10 nicotinic cholinergic receptor by ascorbic acid
dc.creator.none.fl_str_mv Boffi, Juan Carlos
Wedemeyer, Carolina
Lipovsek, Maria Marcela
Katz, Eleonora
Calvo, Daniel Juan
Elgoyhen, Ana Belen
author Boffi, Juan Carlos
author_facet Boffi, Juan Carlos
Wedemeyer, Carolina
Lipovsek, Maria Marcela
Katz, Eleonora
Calvo, Daniel Juan
Elgoyhen, Ana Belen
author_role author
author2 Wedemeyer, Carolina
Lipovsek, Maria Marcela
Katz, Eleonora
Calvo, Daniel Juan
Elgoyhen, Ana Belen
author2_role author
author
author
author
author
dc.subject.none.fl_str_mv Ascorbic Acid
Nicotinic Receptors
Pams
Alpha9alpha10
Ascorbate
Vitamin C
Positive Allosteric Modulator
Redox Modulator
Efferent Olivocochlear
Acoustic Trauma
Hearing Loss
topic Ascorbic Acid
Nicotinic Receptors
Pams
Alpha9alpha10
Ascorbate
Vitamin C
Positive Allosteric Modulator
Redox Modulator
Efferent Olivocochlear
Acoustic Trauma
Hearing Loss
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.6
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv Background and Purpose: The activation of α9α10 nicotinic cholinergic receptors (nAChRs) present at the synapse between efferent olivocochlear fibres and cochlear hair cells can prevent acoustic trauma. Hence, pharmacological potentiators of these receptors could be useful therapeutically. In this work, we characterize ascorbic acid as a positive modulator of recombinant α9α10 nAChRs. Experimental Approach: ACh-evoked responses were analysed under two-electrode voltage-clamp recordings in Xenopus laevis oocytes injected with α9 and α10 cRNAs. Key Results: Ascorbic acid potentiated ACh responses in X. laevis oocytes expressing α9α10 (but not α4β2 or α7) nAChRs, in a concentration-dependent manner, with an effective concentration range of 1–30 mM. The compound did not affect the receptor's current–voltage profile nor its apparent affinity for ACh, but it significantly enhanced the maximal evoked currents (percentage of ACh maximal response, 240 ± 20%). This effect was specific for the L form of reduced ascorbic acid. Substitution of the extracellular cysteine residues present in loop C of the ACh binding site did not affect the potentiation. Ascorbic acid turned into a partial agonist of α9α10 nAChRs bearing a point mutation at the pore domain of the channel (TM2 V13′T mutant). A positive allosteric mechanism of action rather than an antioxidant effect of ascorbic acid is proposed. Conclusions and Implications: The present work describes one of the few agents that activates or potentiates α9α10 nAChRs and leads to new avenues for designing drugs with potential therapeutic use in inner ear disorders.
Fil: Boffi, Juan Carlos. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular; Argentina
Fil: Wedemeyer, Carolina. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular; Argentina
Fil: Lipovsek, Maria Marcela. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular; Argentina
Fil: Katz, Eleonora. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular; Argentina
Fil: Calvo, Daniel Juan. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular; Argentina
Fil: Elgoyhen, Ana Belen. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Farmacología; Argentina
description Background and Purpose: The activation of α9α10 nicotinic cholinergic receptors (nAChRs) present at the synapse between efferent olivocochlear fibres and cochlear hair cells can prevent acoustic trauma. Hence, pharmacological potentiators of these receptors could be useful therapeutically. In this work, we characterize ascorbic acid as a positive modulator of recombinant α9α10 nAChRs. Experimental Approach: ACh-evoked responses were analysed under two-electrode voltage-clamp recordings in Xenopus laevis oocytes injected with α9 and α10 cRNAs. Key Results: Ascorbic acid potentiated ACh responses in X. laevis oocytes expressing α9α10 (but not α4β2 or α7) nAChRs, in a concentration-dependent manner, with an effective concentration range of 1–30 mM. The compound did not affect the receptor's current–voltage profile nor its apparent affinity for ACh, but it significantly enhanced the maximal evoked currents (percentage of ACh maximal response, 240 ± 20%). This effect was specific for the L form of reduced ascorbic acid. Substitution of the extracellular cysteine residues present in loop C of the ACh binding site did not affect the potentiation. Ascorbic acid turned into a partial agonist of α9α10 nAChRs bearing a point mutation at the pore domain of the channel (TM2 V13′T mutant). A positive allosteric mechanism of action rather than an antioxidant effect of ascorbic acid is proposed. Conclusions and Implications: The present work describes one of the few agents that activates or potentiates α9α10 nAChRs and leads to new avenues for designing drugs with potential therapeutic use in inner ear disorders.
publishDate 2013
dc.date.none.fl_str_mv 2013-01-24
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/11336/4012
Boffi, Juan Carlos; Wedemeyer, Carolina; Lipovsek, Maria Marcela; Katz, Eleonora; Calvo, Daniel Juan; et al.; Positive modulation of the a9a10 nicotinic cholinergic receptor by ascorbic acid; Wiley; British Journal of Pharmacology; 168; 4; 24-1-2013; 954-965
1476-5381
url http://hdl.handle.net/11336/4012
identifier_str_mv Boffi, Juan Carlos; Wedemeyer, Carolina; Lipovsek, Maria Marcela; Katz, Eleonora; Calvo, Daniel Juan; et al.; Positive modulation of the a9a10 nicotinic cholinergic receptor by ascorbic acid; Wiley; British Journal of Pharmacology; 168; 4; 24-1-2013; 954-965
1476-5381
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/url/http://onlinelibrary.wiley.com/doi/10.1111/j.1476-5381.2012.02221.x/abstract
info:eu-repo/semantics/altIdentifier/issn/1476-5381
info:eu-repo/semantics/altIdentifier/doi/DOI:10.1111/j.1476-5381.2012.02221.x
info:eu-repo/semantics/altIdentifier/url/http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3631383/
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
dc.publisher.none.fl_str_mv Wiley
publisher.none.fl_str_mv Wiley
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 13.001348

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