Modulation by tyrosine phosphorylation of ionotropic and metabotropic responses of alpha7 nicotinic receptor

Autores
Chrestia, Juan Facundo; Bruzzone, Ariana; Esandi, María del Carmen; Bouzat, Cecilia Beatriz
Año de publicación
2020
Idioma
inglés
Tipo de recurso
documento de conferencia
Estado
versión publicada
Descripción
The α7 nicotinic acetylcholine receptor is present in neuronal and non-neuronal cells. α7 acts as a ligand-gated ion channel and as a metabotropic receptor. Its activity is associated to neurological and neurodegenerative disorders, and it plays a role in neuroprotection and inflammation. Protein phosphorylation is an important regulatory mechanism involved in physiological and pathological processes. We investigated the role of tyrosine phosphorylation of α7 intracellular domain (ICD) in its dual ionotropic/ metabotropic function. In HEK cells expressing α7, single-channel activity appears as brief isolated openings and episodes of few openings in quick succession (bursts). Inhibition of Src family kinases by PP2 as well as co-expression of α7 with an inactive Src kinase increase the duration and frequency of bursts, while inhibition of tyrosine phosphatases with pervanadate decreases open and burst durations without affecting channel amplitude. A mutant α7 lacking phosphorylation sites shows longer burst durations and insensitivity to PP2, thus revealing that the two tyrosine residues in the intracellular domain (ICD) are involved in receptor modulation. Cells exposed to a specific α7 agonist (PNU-282987) show an increase of ERK1/2 phosphorylation, which is detected neither in the presence of Src family kinases inhibitors nor in cells expressing the mutant receptor lacking tyrosines. Thus, phosphorylation negatively modulates ionotropic α7 activity probably by enhancing desensitization whereas the phosphorylated state of α7-ICD is required for the metabotropic receptor responses. Since the ICD is the less conserved domain among pentameric ligand-gated ion channels, potentiation of α7 through its ICD may be an attractive strategy for specific therapies in disorders involving α7.
Fil: Chrestia, Juan Facundo. 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: Bruzzone, Ariana. 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: Esandi, María del Carmen. Universidad Nacional del Sur. Departamento de Biología, Bioquímica y Farmacia; Argentina. 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: 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
Primeras Jornadas Virtuales de la Sociedad Argentina de Biofísica SAB 2020/Biofísica en Tiempos de COVID-19
Buenos Aires
Argentina
Sociedad Argentina de Biofísica
Materia
PHOSPHORYLATION
NICOTINIC RECEPTOR
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:11336/195366
Acceder
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network_name_str CONICET Digital (CONICET)
spelling Modulation by tyrosine phosphorylation of ionotropic and metabotropic responses of alpha7 nicotinic receptorChrestia, Juan FacundoBruzzone, ArianaEsandi, María del CarmenBouzat, Cecilia BeatrizPHOSPHORYLATIONNICOTINIC RECEPTORhttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1The α7 nicotinic acetylcholine receptor is present in neuronal and non-neuronal cells. α7 acts as a ligand-gated ion channel and as a metabotropic receptor. Its activity is associated to neurological and neurodegenerative disorders, and it plays a role in neuroprotection and inflammation. Protein phosphorylation is an important regulatory mechanism involved in physiological and pathological processes. We investigated the role of tyrosine phosphorylation of α7 intracellular domain (ICD) in its dual ionotropic/ metabotropic function. In HEK cells expressing α7, single-channel activity appears as brief isolated openings and episodes of few openings in quick succession (bursts). Inhibition of Src family kinases by PP2 as well as co-expression of α7 with an inactive Src kinase increase the duration and frequency of bursts, while inhibition of tyrosine phosphatases with pervanadate decreases open and burst durations without affecting channel amplitude. A mutant α7 lacking phosphorylation sites shows longer burst durations and insensitivity to PP2, thus revealing that the two tyrosine residues in the intracellular domain (ICD) are involved in receptor modulation. Cells exposed to a specific α7 agonist (PNU-282987) show an increase of ERK1/2 phosphorylation, which is detected neither in the presence of Src family kinases inhibitors nor in cells expressing the mutant receptor lacking tyrosines. Thus, phosphorylation negatively modulates ionotropic α7 activity probably by enhancing desensitization whereas the phosphorylated state of α7-ICD is required for the metabotropic receptor responses. Since the ICD is the less conserved domain among pentameric ligand-gated ion channels, potentiation of α7 through its ICD may be an attractive strategy for specific therapies in disorders involving α7.Fil: Chrestia, Juan Facundo. 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: Bruzzone, Ariana. 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: Esandi, María del Carmen. Universidad Nacional del Sur. Departamento de Biología, Bioquímica y Farmacia; Argentina. 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: 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; ArgentinaPrimeras Jornadas Virtuales de la Sociedad Argentina de Biofísica SAB 2020/Biofísica en Tiempos de COVID-19Buenos AiresArgentinaSociedad Argentina de BiofísicaSociedad Argentina de BiofísicaDelfino, José M.2020info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/conferenceObjectJornadaBookhttp://purl.org/coar/resource_type/c_5794info:ar-repo/semantics/documentoDeConferenciaapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/195366Modulation by tyrosine phosphorylation of ionotropic and metabotropic responses of alpha7 nicotinic receptor; Primeras Jornadas Virtuales de la Sociedad Argentina de Biofísica SAB 2020/Biofísica en Tiempos de COVID-19; Buenos Aires; Argentina; 2020; 43-43978-987-27591-8-6CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://biofisica.org.arinfo:eu-repo/semantics/altIdentifier/url/https://biofisica.org.ar/reuniones-cientificas/reunionsab-previas/Nacionalinfo:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-10-15T14:52:02Zoai:ri.conicet.gov.ar:11336/195366instacron: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:34982025-10-15 14:52:02.649CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Modulation by tyrosine phosphorylation of ionotropic and metabotropic responses of alpha7 nicotinic receptor
title Modulation by tyrosine phosphorylation of ionotropic and metabotropic responses of alpha7 nicotinic receptor
spellingShingle Modulation by tyrosine phosphorylation of ionotropic and metabotropic responses of alpha7 nicotinic receptor
Chrestia, Juan Facundo
PHOSPHORYLATION
NICOTINIC RECEPTOR
title_short Modulation by tyrosine phosphorylation of ionotropic and metabotropic responses of alpha7 nicotinic receptor
title_full Modulation by tyrosine phosphorylation of ionotropic and metabotropic responses of alpha7 nicotinic receptor
title_fullStr Modulation by tyrosine phosphorylation of ionotropic and metabotropic responses of alpha7 nicotinic receptor
title_full_unstemmed Modulation by tyrosine phosphorylation of ionotropic and metabotropic responses of alpha7 nicotinic receptor
title_sort Modulation by tyrosine phosphorylation of ionotropic and metabotropic responses of alpha7 nicotinic receptor
dc.creator.none.fl_str_mv Chrestia, Juan Facundo
Bruzzone, Ariana
Esandi, María del Carmen
Bouzat, Cecilia Beatriz
author Chrestia, Juan Facundo
author_facet Chrestia, Juan Facundo
Bruzzone, Ariana
Esandi, María del Carmen
Bouzat, Cecilia Beatriz
author_role author
author2 Bruzzone, Ariana
Esandi, María del Carmen
Bouzat, Cecilia Beatriz
author2_role author
author
author
dc.contributor.none.fl_str_mv Delfino, José M.
dc.subject.none.fl_str_mv PHOSPHORYLATION
NICOTINIC RECEPTOR
topic PHOSPHORYLATION
NICOTINIC RECEPTOR
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.6
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv The α7 nicotinic acetylcholine receptor is present in neuronal and non-neuronal cells. α7 acts as a ligand-gated ion channel and as a metabotropic receptor. Its activity is associated to neurological and neurodegenerative disorders, and it plays a role in neuroprotection and inflammation. Protein phosphorylation is an important regulatory mechanism involved in physiological and pathological processes. We investigated the role of tyrosine phosphorylation of α7 intracellular domain (ICD) in its dual ionotropic/ metabotropic function. In HEK cells expressing α7, single-channel activity appears as brief isolated openings and episodes of few openings in quick succession (bursts). Inhibition of Src family kinases by PP2 as well as co-expression of α7 with an inactive Src kinase increase the duration and frequency of bursts, while inhibition of tyrosine phosphatases with pervanadate decreases open and burst durations without affecting channel amplitude. A mutant α7 lacking phosphorylation sites shows longer burst durations and insensitivity to PP2, thus revealing that the two tyrosine residues in the intracellular domain (ICD) are involved in receptor modulation. Cells exposed to a specific α7 agonist (PNU-282987) show an increase of ERK1/2 phosphorylation, which is detected neither in the presence of Src family kinases inhibitors nor in cells expressing the mutant receptor lacking tyrosines. Thus, phosphorylation negatively modulates ionotropic α7 activity probably by enhancing desensitization whereas the phosphorylated state of α7-ICD is required for the metabotropic receptor responses. Since the ICD is the less conserved domain among pentameric ligand-gated ion channels, potentiation of α7 through its ICD may be an attractive strategy for specific therapies in disorders involving α7.
Fil: Chrestia, Juan Facundo. 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: Bruzzone, Ariana. 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: Esandi, María del Carmen. Universidad Nacional del Sur. Departamento de Biología, Bioquímica y Farmacia; Argentina. 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: 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
Primeras Jornadas Virtuales de la Sociedad Argentina de Biofísica SAB 2020/Biofísica en Tiempos de COVID-19
Buenos Aires
Argentina
Sociedad Argentina de Biofísica
description The α7 nicotinic acetylcholine receptor is present in neuronal and non-neuronal cells. α7 acts as a ligand-gated ion channel and as a metabotropic receptor. Its activity is associated to neurological and neurodegenerative disorders, and it plays a role in neuroprotection and inflammation. Protein phosphorylation is an important regulatory mechanism involved in physiological and pathological processes. We investigated the role of tyrosine phosphorylation of α7 intracellular domain (ICD) in its dual ionotropic/ metabotropic function. In HEK cells expressing α7, single-channel activity appears as brief isolated openings and episodes of few openings in quick succession (bursts). Inhibition of Src family kinases by PP2 as well as co-expression of α7 with an inactive Src kinase increase the duration and frequency of bursts, while inhibition of tyrosine phosphatases with pervanadate decreases open and burst durations without affecting channel amplitude. A mutant α7 lacking phosphorylation sites shows longer burst durations and insensitivity to PP2, thus revealing that the two tyrosine residues in the intracellular domain (ICD) are involved in receptor modulation. Cells exposed to a specific α7 agonist (PNU-282987) show an increase of ERK1/2 phosphorylation, which is detected neither in the presence of Src family kinases inhibitors nor in cells expressing the mutant receptor lacking tyrosines. Thus, phosphorylation negatively modulates ionotropic α7 activity probably by enhancing desensitization whereas the phosphorylated state of α7-ICD is required for the metabotropic receptor responses. Since the ICD is the less conserved domain among pentameric ligand-gated ion channels, potentiation of α7 through its ICD may be an attractive strategy for specific therapies in disorders involving α7.
publishDate 2020
dc.date.none.fl_str_mv 2020
dc.type.none.fl_str_mv info:eu-repo/semantics/publishedVersion
info:eu-repo/semantics/conferenceObject
Jornada
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/11336/195366
Modulation by tyrosine phosphorylation of ionotropic and metabotropic responses of alpha7 nicotinic receptor; Primeras Jornadas Virtuales de la Sociedad Argentina de Biofísica SAB 2020/Biofísica en Tiempos de COVID-19; Buenos Aires; Argentina; 2020; 43-43
978-987-27591-8-6
CONICET Digital
CONICET
url http://hdl.handle.net/11336/195366
identifier_str_mv Modulation by tyrosine phosphorylation of ionotropic and metabotropic responses of alpha7 nicotinic receptor; Primeras Jornadas Virtuales de la Sociedad Argentina de Biofísica SAB 2020/Biofísica en Tiempos de COVID-19; Buenos Aires; Argentina; 2020; 43-43
978-987-27591-8-6
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
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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 Nacional
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)
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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