Benzodiazepine modulation of homomeric GABAAρ1 receptors: Differential effects of diazepam and 40´-chlorodiazepam

Autores
Andrea Beltrán González; Pomata, Pablo Ernesto; Goutman, Juan Diego; Gasulla, Javier; Chebib, Mary; Calvo, Daniel Juan
Año de publicación
2014
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
GABAA receptors (GABAARs) are ligand-gated ion channels that mediate inhibitory neurotransmission in the central nervous system (CNS). They are members of the Cys-loop receptor family and display marked structural and functional heterogeneity. Many GABAARs receptor subtypes are allosterically modulated by benzodiazepines (BDZs), which are drugs extensively used as anxiolytics, sedative-hypnotics and anticonvulsants. One high-affinity site and at least three additional low-affinity sites for BDZ recognition have been identified in several heteromeric and homomeric variants of the GABAARs (e.g.: alpha1-beta2-gamma2, alpha1beta2/3, beta3, etc.). However, the modulation of homomeric GABAArhoRs by BDZs was not previously revealed, and these receptors, for a long a time, were assumed to be fully insensitive to the actions of these drugs. In the present study, human homomeric GABAArho1 receptors were expressed in Xenopus oocytes and GABA-evoked responses electrophysiologically recorded in the presence or absence of BDZs. GABAArho1 receptor-mediated responses were modulated by diazepam and 4´-chlorodiazepam in the micromolar range, in a concentration-dependent, voltage-independent and reversible manner. Diazepam produced potentiating effects on GABA-evoked Cl(-) currents and 4´-Cl diazepam induced biphasic effects depending on the GABA concentration, whereas Ro15-4513 and alprazolam were negative modulators. BDZ actions were insensitive to flumazenil. Other BDZs showed negligible activity at equivalent experimental conditions. Our results suggest that GABAArho1 receptor function can be selectively and differentially modulated by BDZs.
Fil: Andrea Beltrán González. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular; Argentina
Fil: Pomata, Pablo Ernesto. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular; Argentina
Fil: Goutman, Juan Diego. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular; Argentina
Fil: Gasulla, Javier. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular; Argentina
Fil: Chebib, Mary. 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
Materia
Gaba Receptors
Cys-Loop Receptors
Benzodiazepines
Bicuculline-Insensitive Gaba Receptors
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-nd/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/3944
Acceder
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oai_identifier_str oai:ri.conicet.gov.ar:11336/3944
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Benzodiazepine modulation of homomeric GABAAρ1 receptors: Differential effects of diazepam and 40´-chlorodiazepamAndrea Beltrán GonzálezPomata, Pablo ErnestoGoutman, Juan DiegoGasulla, JavierChebib, MaryCalvo, Daniel JuanGaba ReceptorsCys-Loop ReceptorsBenzodiazepinesBicuculline-Insensitive Gaba Receptorshttps://purl.org/becyt/ford/3.1https://purl.org/becyt/ford/3GABAA receptors (GABAARs) are ligand-gated ion channels that mediate inhibitory neurotransmission in the central nervous system (CNS). They are members of the Cys-loop receptor family and display marked structural and functional heterogeneity. Many GABAARs receptor subtypes are allosterically modulated by benzodiazepines (BDZs), which are drugs extensively used as anxiolytics, sedative-hypnotics and anticonvulsants. One high-affinity site and at least three additional low-affinity sites for BDZ recognition have been identified in several heteromeric and homomeric variants of the GABAARs (e.g.: alpha1-beta2-gamma2, alpha1beta2/3, beta3, etc.). However, the modulation of homomeric GABAArhoRs by BDZs was not previously revealed, and these receptors, for a long a time, were assumed to be fully insensitive to the actions of these drugs. In the present study, human homomeric GABAArho1 receptors were expressed in Xenopus oocytes and GABA-evoked responses electrophysiologically recorded in the presence or absence of BDZs. GABAArho1 receptor-mediated responses were modulated by diazepam and 4´-chlorodiazepam in the micromolar range, in a concentration-dependent, voltage-independent and reversible manner. Diazepam produced potentiating effects on GABA-evoked Cl(-) currents and 4´-Cl diazepam induced biphasic effects depending on the GABA concentration, whereas Ro15-4513 and alprazolam were negative modulators. BDZ actions were insensitive to flumazenil. Other BDZs showed negligible activity at equivalent experimental conditions. Our results suggest that GABAArho1 receptor function can be selectively and differentially modulated by BDZs.Fil: Andrea Beltrán González. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular; ArgentinaFil: Pomata, Pablo Ernesto. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular; ArgentinaFil: Goutman, Juan Diego. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular; ArgentinaFil: Gasulla, Javier. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular; ArgentinaFil: Chebib, Mary. 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; ArgentinaElsevier2014-09-22info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/mswordapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/3944Andrea Beltrán González; Pomata, Pablo Ernesto; Goutman, Juan Diego; Gasulla, Javier; Chebib, Mary; et al.; Benzodiazepine modulation of homomeric GABAAρ1 receptors: Differential effects of diazepam and 40´-chlorodiazepam; Elsevier; European Journal of Pharmacology; 743; 22-9-2014; 24-300014-2999enginfo:eu-repo/semantics/altIdentifier/url/http://www.sciencedirect.com/science/article/pii/S001429991400661Xinfo:eu-repo/semantics/altIdentifier/doi/10.1016/j.ejphar.2014.09.017info:eu-repo/semantics/altIdentifier/ark/0014-2999info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-nd/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-29T10:17:48Zoai:ri.conicet.gov.ar:11336/3944instacron: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 10:17:49.067CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Benzodiazepine modulation of homomeric GABAAρ1 receptors: Differential effects of diazepam and 40´-chlorodiazepam
title Benzodiazepine modulation of homomeric GABAAρ1 receptors: Differential effects of diazepam and 40´-chlorodiazepam
spellingShingle Benzodiazepine modulation of homomeric GABAAρ1 receptors: Differential effects of diazepam and 40´-chlorodiazepam
Andrea Beltrán González
Gaba Receptors
Cys-Loop Receptors
Benzodiazepines
Bicuculline-Insensitive Gaba Receptors
title_short Benzodiazepine modulation of homomeric GABAAρ1 receptors: Differential effects of diazepam and 40´-chlorodiazepam
title_full Benzodiazepine modulation of homomeric GABAAρ1 receptors: Differential effects of diazepam and 40´-chlorodiazepam
title_fullStr Benzodiazepine modulation of homomeric GABAAρ1 receptors: Differential effects of diazepam and 40´-chlorodiazepam
title_full_unstemmed Benzodiazepine modulation of homomeric GABAAρ1 receptors: Differential effects of diazepam and 40´-chlorodiazepam
title_sort Benzodiazepine modulation of homomeric GABAAρ1 receptors: Differential effects of diazepam and 40´-chlorodiazepam
dc.creator.none.fl_str_mv Andrea Beltrán González
Pomata, Pablo Ernesto
Goutman, Juan Diego
Gasulla, Javier
Chebib, Mary
Calvo, Daniel Juan
author Andrea Beltrán González
author_facet Andrea Beltrán González
Pomata, Pablo Ernesto
Goutman, Juan Diego
Gasulla, Javier
Chebib, Mary
Calvo, Daniel Juan
author_role author
author2 Pomata, Pablo Ernesto
Goutman, Juan Diego
Gasulla, Javier
Chebib, Mary
Calvo, Daniel Juan
author2_role author
author
author
author
author
dc.subject.none.fl_str_mv Gaba Receptors
Cys-Loop Receptors
Benzodiazepines
Bicuculline-Insensitive Gaba Receptors
topic Gaba Receptors
Cys-Loop Receptors
Benzodiazepines
Bicuculline-Insensitive Gaba Receptors
purl_subject.fl_str_mv https://purl.org/becyt/ford/3.1
https://purl.org/becyt/ford/3
dc.description.none.fl_txt_mv GABAA receptors (GABAARs) are ligand-gated ion channels that mediate inhibitory neurotransmission in the central nervous system (CNS). They are members of the Cys-loop receptor family and display marked structural and functional heterogeneity. Many GABAARs receptor subtypes are allosterically modulated by benzodiazepines (BDZs), which are drugs extensively used as anxiolytics, sedative-hypnotics and anticonvulsants. One high-affinity site and at least three additional low-affinity sites for BDZ recognition have been identified in several heteromeric and homomeric variants of the GABAARs (e.g.: alpha1-beta2-gamma2, alpha1beta2/3, beta3, etc.). However, the modulation of homomeric GABAArhoRs by BDZs was not previously revealed, and these receptors, for a long a time, were assumed to be fully insensitive to the actions of these drugs. In the present study, human homomeric GABAArho1 receptors were expressed in Xenopus oocytes and GABA-evoked responses electrophysiologically recorded in the presence or absence of BDZs. GABAArho1 receptor-mediated responses were modulated by diazepam and 4´-chlorodiazepam in the micromolar range, in a concentration-dependent, voltage-independent and reversible manner. Diazepam produced potentiating effects on GABA-evoked Cl(-) currents and 4´-Cl diazepam induced biphasic effects depending on the GABA concentration, whereas Ro15-4513 and alprazolam were negative modulators. BDZ actions were insensitive to flumazenil. Other BDZs showed negligible activity at equivalent experimental conditions. Our results suggest that GABAArho1 receptor function can be selectively and differentially modulated by BDZs.
Fil: Andrea Beltrán González. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular; Argentina
Fil: Pomata, Pablo Ernesto. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular; Argentina
Fil: Goutman, Juan Diego. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular; Argentina
Fil: Gasulla, Javier. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular; Argentina
Fil: Chebib, Mary. 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
description GABAA receptors (GABAARs) are ligand-gated ion channels that mediate inhibitory neurotransmission in the central nervous system (CNS). They are members of the Cys-loop receptor family and display marked structural and functional heterogeneity. Many GABAARs receptor subtypes are allosterically modulated by benzodiazepines (BDZs), which are drugs extensively used as anxiolytics, sedative-hypnotics and anticonvulsants. One high-affinity site and at least three additional low-affinity sites for BDZ recognition have been identified in several heteromeric and homomeric variants of the GABAARs (e.g.: alpha1-beta2-gamma2, alpha1beta2/3, beta3, etc.). However, the modulation of homomeric GABAArhoRs by BDZs was not previously revealed, and these receptors, for a long a time, were assumed to be fully insensitive to the actions of these drugs. In the present study, human homomeric GABAArho1 receptors were expressed in Xenopus oocytes and GABA-evoked responses electrophysiologically recorded in the presence or absence of BDZs. GABAArho1 receptor-mediated responses were modulated by diazepam and 4´-chlorodiazepam in the micromolar range, in a concentration-dependent, voltage-independent and reversible manner. Diazepam produced potentiating effects on GABA-evoked Cl(-) currents and 4´-Cl diazepam induced biphasic effects depending on the GABA concentration, whereas Ro15-4513 and alprazolam were negative modulators. BDZ actions were insensitive to flumazenil. Other BDZs showed negligible activity at equivalent experimental conditions. Our results suggest that GABAArho1 receptor function can be selectively and differentially modulated by BDZs.
publishDate 2014
dc.date.none.fl_str_mv 2014-09-22
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/11336/3944
Andrea Beltrán González; Pomata, Pablo Ernesto; Goutman, Juan Diego; Gasulla, Javier; Chebib, Mary; et al.; Benzodiazepine modulation of homomeric GABAAρ1 receptors: Differential effects of diazepam and 40´-chlorodiazepam; Elsevier; European Journal of Pharmacology; 743; 22-9-2014; 24-30
0014-2999
url http://hdl.handle.net/11336/3944
identifier_str_mv Andrea Beltrán González; Pomata, Pablo Ernesto; Goutman, Juan Diego; Gasulla, Javier; Chebib, Mary; et al.; Benzodiazepine modulation of homomeric GABAAρ1 receptors: Differential effects of diazepam and 40´-chlorodiazepam; Elsevier; European Journal of Pharmacology; 743; 22-9-2014; 24-30
0014-2999
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/url/http://www.sciencedirect.com/science/article/pii/S001429991400661X
info:eu-repo/semantics/altIdentifier/doi/10.1016/j.ejphar.2014.09.017
info:eu-repo/semantics/altIdentifier/ark/0014-2999
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc-nd/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-nd/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/msword
application/pdf
application/pdf
application/pdf
dc.publisher.none.fl_str_mv Elsevier
publisher.none.fl_str_mv Elsevier
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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