GABA-induced uncoupling of GABA/benzodiazepine site interactions is associated with increased phosphorylation of the GABAA receptor

Autores
Gutiérrez, María Laura; Ferreri, Maria Celeste; Farb, David H.; Gravielle, Maria Clara
Año de publicación
2014
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
The use-dependent regulation of the GABAA receptor occurs under physiological, pathological, and pharmacological conditions. Tolerance induced by prolonged administration of benzodiazepines is associated with changes in GABAA receptor function. Chronic exposure of neurons to GABA for 48 hr induces a downregulation of the GABAA receptor number and an uncoupling of the GABA/benzodiazepine site interactions. A single brief exposure (t1/2 = 3 min) of rat neocortical neurons to the neurotransmitter initiates a process that results in uncoupling hours later (t1/2 = 12 hr) without alterations in the number of GABAA receptors and provides a paradigm to study the uncoupling mechanism selectively. Here we report that uncoupling induced by a brief GABAA receptor activation is blocked by the coincubation with inhibitors of protein kinases A and C, indicating that the uncoupling is mediated by the activation of a phosphorylation cascade. GABA-induced uncoupling is accompanied by subunit-selective changes in the GABAA receptor mRNA levels. However, the GABA-induced downregulation of the α3 subunit mRNA level is not altered by the kinase inhibitors, suggesting that the uncoupling is the result of a posttranscriptional regulatory process. GABA exposure also produces an increase in the serine phosphorylation on the GABAA receptor γ2 subunit. Taken together, our results suggest that the GABA-induced uncoupling is mediated by a posttranscriptional mechanism involving an increase in the phosphorylation of GABAA receptors. The uncoupling of the GABAA receptor may represent a compensatory mechanism to control GABAergic neurotransmission under conditions in which receptors are persistently activated.
Fil: Gutiérrez, María Laura. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Farmacológicas (i); Argentina
Fil: Ferreri, Maria Celeste. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Farmacológicas (i); Argentina
Fil: Farb, David H.. Boston University; Estados Unidos
Fil: Gravielle, Maria Clara. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Farmacológicas (i); Argentina
Materia
Gabaa Receptors
Gaba
Post Translational Modification
Plasticity
Uncoupling
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:11336/13635
Acceder
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oai_identifier_str oai:ri.conicet.gov.ar:11336/13635
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling GABA-induced uncoupling of GABA/benzodiazepine site interactions is associated with increased phosphorylation of the GABAA receptorGutiérrez, María LauraFerreri, Maria CelesteFarb, David H.Gravielle, Maria ClaraGabaa ReceptorsGabaPost Translational ModificationPlasticityUncouplinghttps://purl.org/becyt/ford/3.1https://purl.org/becyt/ford/3The use-dependent regulation of the GABAA receptor occurs under physiological, pathological, and pharmacological conditions. Tolerance induced by prolonged administration of benzodiazepines is associated with changes in GABAA receptor function. Chronic exposure of neurons to GABA for 48 hr induces a downregulation of the GABAA receptor number and an uncoupling of the GABA/benzodiazepine site interactions. A single brief exposure (t1/2 = 3 min) of rat neocortical neurons to the neurotransmitter initiates a process that results in uncoupling hours later (t1/2 = 12 hr) without alterations in the number of GABAA receptors and provides a paradigm to study the uncoupling mechanism selectively. Here we report that uncoupling induced by a brief GABAA receptor activation is blocked by the coincubation with inhibitors of protein kinases A and C, indicating that the uncoupling is mediated by the activation of a phosphorylation cascade. GABA-induced uncoupling is accompanied by subunit-selective changes in the GABAA receptor mRNA levels. However, the GABA-induced downregulation of the α3 subunit mRNA level is not altered by the kinase inhibitors, suggesting that the uncoupling is the result of a posttranscriptional regulatory process. GABA exposure also produces an increase in the serine phosphorylation on the GABAA receptor γ2 subunit. Taken together, our results suggest that the GABA-induced uncoupling is mediated by a posttranscriptional mechanism involving an increase in the phosphorylation of GABAA receptors. The uncoupling of the GABAA receptor may represent a compensatory mechanism to control GABAergic neurotransmission under conditions in which receptors are persistently activated.Fil: Gutiérrez, María Laura. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Farmacológicas (i); ArgentinaFil: Ferreri, Maria Celeste. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Farmacológicas (i); ArgentinaFil: Farb, David H.. Boston University; Estados UnidosFil: Gravielle, Maria Clara. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Farmacológicas (i); ArgentinaWiley2014-08info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/13635Gutiérrez, María Laura; Ferreri, Maria Celeste; Farb, David H.; Gravielle, Maria Clara; GABA-induced uncoupling of GABA/benzodiazepine site interactions is associated with increased phosphorylation of the GABAA receptor; Wiley; Journal of Neuroscience Research; 92; 8; 8-2014; 1054-10610360-4012enginfo:eu-repo/semantics/altIdentifier/url/http://onlinelibrary.wiley.com/doi/10.1002/jnr.23387/abstractinfo:eu-repo/semantics/altIdentifier/doi/10.1002/jnr.23387info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-29T09:53:02Zoai:ri.conicet.gov.ar:11336/13635instacron: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:34982025-09-29 09:53:02.779CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv GABA-induced uncoupling of GABA/benzodiazepine site interactions is associated with increased phosphorylation of the GABAA receptor
title GABA-induced uncoupling of GABA/benzodiazepine site interactions is associated with increased phosphorylation of the GABAA receptor
spellingShingle GABA-induced uncoupling of GABA/benzodiazepine site interactions is associated with increased phosphorylation of the GABAA receptor
Gutiérrez, María Laura
Gabaa Receptors
Gaba
Post Translational Modification
Plasticity
Uncoupling
title_short GABA-induced uncoupling of GABA/benzodiazepine site interactions is associated with increased phosphorylation of the GABAA receptor
title_full GABA-induced uncoupling of GABA/benzodiazepine site interactions is associated with increased phosphorylation of the GABAA receptor
title_fullStr GABA-induced uncoupling of GABA/benzodiazepine site interactions is associated with increased phosphorylation of the GABAA receptor
title_full_unstemmed GABA-induced uncoupling of GABA/benzodiazepine site interactions is associated with increased phosphorylation of the GABAA receptor
title_sort GABA-induced uncoupling of GABA/benzodiazepine site interactions is associated with increased phosphorylation of the GABAA receptor
dc.creator.none.fl_str_mv Gutiérrez, María Laura
Ferreri, Maria Celeste
Farb, David H.
Gravielle, Maria Clara
author Gutiérrez, María Laura
author_facet Gutiérrez, María Laura
Ferreri, Maria Celeste
Farb, David H.
Gravielle, Maria Clara
author_role author
author2 Ferreri, Maria Celeste
Farb, David H.
Gravielle, Maria Clara
author2_role author
author
author
dc.subject.none.fl_str_mv Gabaa Receptors
Gaba
Post Translational Modification
Plasticity
Uncoupling
topic Gabaa Receptors
Gaba
Post Translational Modification
Plasticity
Uncoupling
purl_subject.fl_str_mv https://purl.org/becyt/ford/3.1
https://purl.org/becyt/ford/3
dc.description.none.fl_txt_mv The use-dependent regulation of the GABAA receptor occurs under physiological, pathological, and pharmacological conditions. Tolerance induced by prolonged administration of benzodiazepines is associated with changes in GABAA receptor function. Chronic exposure of neurons to GABA for 48 hr induces a downregulation of the GABAA receptor number and an uncoupling of the GABA/benzodiazepine site interactions. A single brief exposure (t1/2 = 3 min) of rat neocortical neurons to the neurotransmitter initiates a process that results in uncoupling hours later (t1/2 = 12 hr) without alterations in the number of GABAA receptors and provides a paradigm to study the uncoupling mechanism selectively. Here we report that uncoupling induced by a brief GABAA receptor activation is blocked by the coincubation with inhibitors of protein kinases A and C, indicating that the uncoupling is mediated by the activation of a phosphorylation cascade. GABA-induced uncoupling is accompanied by subunit-selective changes in the GABAA receptor mRNA levels. However, the GABA-induced downregulation of the α3 subunit mRNA level is not altered by the kinase inhibitors, suggesting that the uncoupling is the result of a posttranscriptional regulatory process. GABA exposure also produces an increase in the serine phosphorylation on the GABAA receptor γ2 subunit. Taken together, our results suggest that the GABA-induced uncoupling is mediated by a posttranscriptional mechanism involving an increase in the phosphorylation of GABAA receptors. The uncoupling of the GABAA receptor may represent a compensatory mechanism to control GABAergic neurotransmission under conditions in which receptors are persistently activated.
Fil: Gutiérrez, María Laura. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Farmacológicas (i); Argentina
Fil: Ferreri, Maria Celeste. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Farmacológicas (i); Argentina
Fil: Farb, David H.. Boston University; Estados Unidos
Fil: Gravielle, Maria Clara. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Farmacológicas (i); Argentina
description The use-dependent regulation of the GABAA receptor occurs under physiological, pathological, and pharmacological conditions. Tolerance induced by prolonged administration of benzodiazepines is associated with changes in GABAA receptor function. Chronic exposure of neurons to GABA for 48 hr induces a downregulation of the GABAA receptor number and an uncoupling of the GABA/benzodiazepine site interactions. A single brief exposure (t1/2 = 3 min) of rat neocortical neurons to the neurotransmitter initiates a process that results in uncoupling hours later (t1/2 = 12 hr) without alterations in the number of GABAA receptors and provides a paradigm to study the uncoupling mechanism selectively. Here we report that uncoupling induced by a brief GABAA receptor activation is blocked by the coincubation with inhibitors of protein kinases A and C, indicating that the uncoupling is mediated by the activation of a phosphorylation cascade. GABA-induced uncoupling is accompanied by subunit-selective changes in the GABAA receptor mRNA levels. However, the GABA-induced downregulation of the α3 subunit mRNA level is not altered by the kinase inhibitors, suggesting that the uncoupling is the result of a posttranscriptional regulatory process. GABA exposure also produces an increase in the serine phosphorylation on the GABAA receptor γ2 subunit. Taken together, our results suggest that the GABA-induced uncoupling is mediated by a posttranscriptional mechanism involving an increase in the phosphorylation of GABAA receptors. The uncoupling of the GABAA receptor may represent a compensatory mechanism to control GABAergic neurotransmission under conditions in which receptors are persistently activated.
publishDate 2014
dc.date.none.fl_str_mv 2014-08
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/11336/13635
Gutiérrez, María Laura; Ferreri, Maria Celeste; Farb, David H.; Gravielle, Maria Clara; GABA-induced uncoupling of GABA/benzodiazepine site interactions is associated with increased phosphorylation of the GABAA receptor; Wiley; Journal of Neuroscience Research; 92; 8; 8-2014; 1054-1061
0360-4012
url http://hdl.handle.net/11336/13635
identifier_str_mv Gutiérrez, María Laura; Ferreri, Maria Celeste; Farb, David H.; Gravielle, Maria Clara; GABA-induced uncoupling of GABA/benzodiazepine site interactions is associated with increased phosphorylation of the GABAA receptor; Wiley; Journal of Neuroscience Research; 92; 8; 8-2014; 1054-1061
0360-4012
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/10.1002/jnr.23387/abstract
info:eu-repo/semantics/altIdentifier/doi/10.1002/jnr.23387
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
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 13.070432

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