Constitutive activity of the dopamine (D5) receptor, highly expressed in CA1 hippocampal neurons, selectively reduces CaV3.2 and CaV3.3 currents

Autores
Mustafá, Emilio Román; Mccarthy, Clara Inés; Portales, Andrea; Cordisco Gonzalez, Santiago; Rodríguez, Silvia Susana; Raingo, Jesica
Año de publicación
2022
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Background and Purpose: CaV3.1-3 currents differentially contribute to neuronal firing patterns. CaV3 are regulated by G protein-coupled receptors (GPCRs) activity, but information about CaV3 as targets of the constitutive activity of GPCRs is scarce. We investigate the impact of D5 recpetor constitutive activity, a GPCR with high levels of basal activity, on CaV3 functionality. D5 recpetor and CaV3 are expressed in the hippocampus and have been independently linked to pathophysiological states associated with epilepsy. Experimental Approach: Our study models were HEK293T cells heterologously expressing D1 or D5 receptor and CaV3.1-3, and mouse brain slices containing the hippocampus. We used chlorpromazine (D1/D5 inverse agonist) and a D5 receptor mutant lacking constitutive activity as experimental tools. We measured CaV3 currents and excitability parameters using the patch-clamp technique. We completed our study with computational modelling and imaging technique. Key Results: We found a higher sensitivity to TTA-P2 (CaV3 blocker) in CA1 pyramidal neurons obtained from chlorpromazine-treated animals compared with vehicle-treated animals. We found that CaV3.2 and CaV3.3—but not CaV3.1—are targets of D5 receptor constitutive activity in HEK293T cells. Finally, we found an increased firing rate in CA1 pyramidal neurons from chlorpromazine-treated animals in comparison with vehicle-treated animals. Similar changes in firing rate were observed on a neuronal model with controlled CaV3 currents levels. Conclusions and Implications: Native hippocampal CaV3 and recombinant CaV3.2-3 are sensitive to D5 receptor constitutive activity. Manipulation of D5 receptor constitutive activity could be a valuable strategy to control neuronal excitability, especially in exacerbated conditions such as epilepsy.
Fil: Mustafá, Emilio Román. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto Multidisciplinario de Biología Celular. Provincia de Buenos Aires. Gobernación. Comisión de Investigaciones Científicas. Instituto Multidisciplinario de Biología Celular. Universidad Nacional de La Plata. Instituto Multidisciplinario de Biología Celular; Argentina
Fil: Mccarthy, Clara Inés. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto Multidisciplinario de Biología Celular. Provincia de Buenos Aires. Gobernación. Comisión de Investigaciones Científicas. Instituto Multidisciplinario de Biología Celular. Universidad Nacional de La Plata. Instituto Multidisciplinario de Biología Celular; Argentina
Fil: Portales, Andrea. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto Multidisciplinario de Biología Celular. Provincia de Buenos Aires. Gobernación. Comisión de Investigaciones Científicas. Instituto Multidisciplinario de Biología Celular. Universidad Nacional de La Plata. Instituto Multidisciplinario de Biología Celular; Argentina
Fil: Cordisco Gonzalez, Santiago. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto Multidisciplinario de Biología Celular. Provincia de Buenos Aires. Gobernación. Comisión de Investigaciones Científicas. Instituto Multidisciplinario de Biología Celular. Universidad Nacional de La Plata. Instituto Multidisciplinario de Biología Celular; Argentina
Fil: Rodríguez, Silvia Susana. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto Multidisciplinario de Biología Celular. Provincia de Buenos Aires. Gobernación. Comisión de Investigaciones Científicas. Instituto Multidisciplinario de Biología Celular. Universidad Nacional de La Plata. Instituto Multidisciplinario de Biología Celular; Argentina
Fil: Raingo, Jesica. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto Multidisciplinario de Biología Celular. Provincia de Buenos Aires. Gobernación. Comisión de Investigaciones Científicas. Instituto Multidisciplinario de Biología Celular. Universidad Nacional de La Plata. Instituto Multidisciplinario de Biología Celular; Argentina
Materia
CAV3.2
CAV3.3
CHLORPROMAZINE
CONSTITUTIVE ACTIVITY
D5 RECEPTOR
HIPPOCAMPUS
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:11336/211497
Acceder
id CONICETDig_e390857b42086c0d22932e19923cdfc4
oai_identifier_str oai:ri.conicet.gov.ar:11336/211497
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Constitutive activity of the dopamine (D5) receptor, highly expressed in CA1 hippocampal neurons, selectively reduces CaV3.2 and CaV3.3 currentsMustafá, Emilio RománMccarthy, Clara InésPortales, AndreaCordisco Gonzalez, SantiagoRodríguez, Silvia SusanaRaingo, JesicaCAV3.2CAV3.3CHLORPROMAZINECONSTITUTIVE ACTIVITYD5 RECEPTORHIPPOCAMPUShttps://purl.org/becyt/ford/3.1https://purl.org/becyt/ford/3Background and Purpose: CaV3.1-3 currents differentially contribute to neuronal firing patterns. CaV3 are regulated by G protein-coupled receptors (GPCRs) activity, but information about CaV3 as targets of the constitutive activity of GPCRs is scarce. We investigate the impact of D5 recpetor constitutive activity, a GPCR with high levels of basal activity, on CaV3 functionality. D5 recpetor and CaV3 are expressed in the hippocampus and have been independently linked to pathophysiological states associated with epilepsy. Experimental Approach: Our study models were HEK293T cells heterologously expressing D1 or D5 receptor and CaV3.1-3, and mouse brain slices containing the hippocampus. We used chlorpromazine (D1/D5 inverse agonist) and a D5 receptor mutant lacking constitutive activity as experimental tools. We measured CaV3 currents and excitability parameters using the patch-clamp technique. We completed our study with computational modelling and imaging technique. Key Results: We found a higher sensitivity to TTA-P2 (CaV3 blocker) in CA1 pyramidal neurons obtained from chlorpromazine-treated animals compared with vehicle-treated animals. We found that CaV3.2 and CaV3.3—but not CaV3.1—are targets of D5 receptor constitutive activity in HEK293T cells. Finally, we found an increased firing rate in CA1 pyramidal neurons from chlorpromazine-treated animals in comparison with vehicle-treated animals. Similar changes in firing rate were observed on a neuronal model with controlled CaV3 currents levels. Conclusions and Implications: Native hippocampal CaV3 and recombinant CaV3.2-3 are sensitive to D5 receptor constitutive activity. Manipulation of D5 receptor constitutive activity could be a valuable strategy to control neuronal excitability, especially in exacerbated conditions such as epilepsy.Fil: Mustafá, Emilio Román. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto Multidisciplinario de Biología Celular. Provincia de Buenos Aires. Gobernación. Comisión de Investigaciones Científicas. Instituto Multidisciplinario de Biología Celular. Universidad Nacional de La Plata. Instituto Multidisciplinario de Biología Celular; ArgentinaFil: Mccarthy, Clara Inés. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto Multidisciplinario de Biología Celular. Provincia de Buenos Aires. Gobernación. Comisión de Investigaciones Científicas. Instituto Multidisciplinario de Biología Celular. Universidad Nacional de La Plata. Instituto Multidisciplinario de Biología Celular; ArgentinaFil: Portales, Andrea. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto Multidisciplinario de Biología Celular. Provincia de Buenos Aires. Gobernación. Comisión de Investigaciones Científicas. Instituto Multidisciplinario de Biología Celular. Universidad Nacional de La Plata. Instituto Multidisciplinario de Biología Celular; ArgentinaFil: Cordisco Gonzalez, Santiago. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto Multidisciplinario de Biología Celular. Provincia de Buenos Aires. Gobernación. Comisión de Investigaciones Científicas. Instituto Multidisciplinario de Biología Celular. Universidad Nacional de La Plata. Instituto Multidisciplinario de Biología Celular; ArgentinaFil: Rodríguez, Silvia Susana. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto Multidisciplinario de Biología Celular. Provincia de Buenos Aires. Gobernación. Comisión de Investigaciones Científicas. Instituto Multidisciplinario de Biología Celular. Universidad Nacional de La Plata. Instituto Multidisciplinario de Biología Celular; ArgentinaFil: Raingo, Jesica. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto Multidisciplinario de Biología Celular. Provincia de Buenos Aires. Gobernación. Comisión de Investigaciones Científicas. Instituto Multidisciplinario de Biología Celular. Universidad Nacional de La Plata. Instituto Multidisciplinario de Biología Celular; ArgentinaWiley Blackwell Publishing, Inc2022-12info: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/11336/211497Mustafá, Emilio Román; Mccarthy, Clara Inés; Portales, Andrea; Cordisco Gonzalez, Santiago; Rodríguez, Silvia Susana; et al.; Constitutive activity of the dopamine (D5) receptor, highly expressed in CA1 hippocampal neurons, selectively reduces CaV3.2 and CaV3.3 currents; Wiley Blackwell Publishing, Inc; British Journal of Pharmacology; 180; 9; 12-2022; 1210-12310007-1188CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://onlinelibrary.wiley.com/doi/10.1111/bph.16006info:eu-repo/semantics/altIdentifier/doi/10.1111/bph.16006info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-29T10:16:36Zoai:ri.conicet.gov.ar:11336/211497instacron: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 10:16:36.8CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Constitutive activity of the dopamine (D5) receptor, highly expressed in CA1 hippocampal neurons, selectively reduces CaV3.2 and CaV3.3 currents
title Constitutive activity of the dopamine (D5) receptor, highly expressed in CA1 hippocampal neurons, selectively reduces CaV3.2 and CaV3.3 currents
spellingShingle Constitutive activity of the dopamine (D5) receptor, highly expressed in CA1 hippocampal neurons, selectively reduces CaV3.2 and CaV3.3 currents
Mustafá, Emilio Román
CAV3.2
CAV3.3
CHLORPROMAZINE
CONSTITUTIVE ACTIVITY
D5 RECEPTOR
HIPPOCAMPUS
title_short Constitutive activity of the dopamine (D5) receptor, highly expressed in CA1 hippocampal neurons, selectively reduces CaV3.2 and CaV3.3 currents
title_full Constitutive activity of the dopamine (D5) receptor, highly expressed in CA1 hippocampal neurons, selectively reduces CaV3.2 and CaV3.3 currents
title_fullStr Constitutive activity of the dopamine (D5) receptor, highly expressed in CA1 hippocampal neurons, selectively reduces CaV3.2 and CaV3.3 currents
title_full_unstemmed Constitutive activity of the dopamine (D5) receptor, highly expressed in CA1 hippocampal neurons, selectively reduces CaV3.2 and CaV3.3 currents
title_sort Constitutive activity of the dopamine (D5) receptor, highly expressed in CA1 hippocampal neurons, selectively reduces CaV3.2 and CaV3.3 currents
dc.creator.none.fl_str_mv Mustafá, Emilio Román
Mccarthy, Clara Inés
Portales, Andrea
Cordisco Gonzalez, Santiago
Rodríguez, Silvia Susana
Raingo, Jesica
author Mustafá, Emilio Román
author_facet Mustafá, Emilio Román
Mccarthy, Clara Inés
Portales, Andrea
Cordisco Gonzalez, Santiago
Rodríguez, Silvia Susana
Raingo, Jesica
author_role author
author2 Mccarthy, Clara Inés
Portales, Andrea
Cordisco Gonzalez, Santiago
Rodríguez, Silvia Susana
Raingo, Jesica
author2_role author
author
author
author
author
dc.subject.none.fl_str_mv CAV3.2
CAV3.3
CHLORPROMAZINE
CONSTITUTIVE ACTIVITY
D5 RECEPTOR
HIPPOCAMPUS
topic CAV3.2
CAV3.3
CHLORPROMAZINE
CONSTITUTIVE ACTIVITY
D5 RECEPTOR
HIPPOCAMPUS
purl_subject.fl_str_mv https://purl.org/becyt/ford/3.1
https://purl.org/becyt/ford/3
dc.description.none.fl_txt_mv Background and Purpose: CaV3.1-3 currents differentially contribute to neuronal firing patterns. CaV3 are regulated by G protein-coupled receptors (GPCRs) activity, but information about CaV3 as targets of the constitutive activity of GPCRs is scarce. We investigate the impact of D5 recpetor constitutive activity, a GPCR with high levels of basal activity, on CaV3 functionality. D5 recpetor and CaV3 are expressed in the hippocampus and have been independently linked to pathophysiological states associated with epilepsy. Experimental Approach: Our study models were HEK293T cells heterologously expressing D1 or D5 receptor and CaV3.1-3, and mouse brain slices containing the hippocampus. We used chlorpromazine (D1/D5 inverse agonist) and a D5 receptor mutant lacking constitutive activity as experimental tools. We measured CaV3 currents and excitability parameters using the patch-clamp technique. We completed our study with computational modelling and imaging technique. Key Results: We found a higher sensitivity to TTA-P2 (CaV3 blocker) in CA1 pyramidal neurons obtained from chlorpromazine-treated animals compared with vehicle-treated animals. We found that CaV3.2 and CaV3.3—but not CaV3.1—are targets of D5 receptor constitutive activity in HEK293T cells. Finally, we found an increased firing rate in CA1 pyramidal neurons from chlorpromazine-treated animals in comparison with vehicle-treated animals. Similar changes in firing rate were observed on a neuronal model with controlled CaV3 currents levels. Conclusions and Implications: Native hippocampal CaV3 and recombinant CaV3.2-3 are sensitive to D5 receptor constitutive activity. Manipulation of D5 receptor constitutive activity could be a valuable strategy to control neuronal excitability, especially in exacerbated conditions such as epilepsy.
Fil: Mustafá, Emilio Román. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto Multidisciplinario de Biología Celular. Provincia de Buenos Aires. Gobernación. Comisión de Investigaciones Científicas. Instituto Multidisciplinario de Biología Celular. Universidad Nacional de La Plata. Instituto Multidisciplinario de Biología Celular; Argentina
Fil: Mccarthy, Clara Inés. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto Multidisciplinario de Biología Celular. Provincia de Buenos Aires. Gobernación. Comisión de Investigaciones Científicas. Instituto Multidisciplinario de Biología Celular. Universidad Nacional de La Plata. Instituto Multidisciplinario de Biología Celular; Argentina
Fil: Portales, Andrea. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto Multidisciplinario de Biología Celular. Provincia de Buenos Aires. Gobernación. Comisión de Investigaciones Científicas. Instituto Multidisciplinario de Biología Celular. Universidad Nacional de La Plata. Instituto Multidisciplinario de Biología Celular; Argentina
Fil: Cordisco Gonzalez, Santiago. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto Multidisciplinario de Biología Celular. Provincia de Buenos Aires. Gobernación. Comisión de Investigaciones Científicas. Instituto Multidisciplinario de Biología Celular. Universidad Nacional de La Plata. Instituto Multidisciplinario de Biología Celular; Argentina
Fil: Rodríguez, Silvia Susana. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto Multidisciplinario de Biología Celular. Provincia de Buenos Aires. Gobernación. Comisión de Investigaciones Científicas. Instituto Multidisciplinario de Biología Celular. Universidad Nacional de La Plata. Instituto Multidisciplinario de Biología Celular; Argentina
Fil: Raingo, Jesica. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto Multidisciplinario de Biología Celular. Provincia de Buenos Aires. Gobernación. Comisión de Investigaciones Científicas. Instituto Multidisciplinario de Biología Celular. Universidad Nacional de La Plata. Instituto Multidisciplinario de Biología Celular; Argentina
description Background and Purpose: CaV3.1-3 currents differentially contribute to neuronal firing patterns. CaV3 are regulated by G protein-coupled receptors (GPCRs) activity, but information about CaV3 as targets of the constitutive activity of GPCRs is scarce. We investigate the impact of D5 recpetor constitutive activity, a GPCR with high levels of basal activity, on CaV3 functionality. D5 recpetor and CaV3 are expressed in the hippocampus and have been independently linked to pathophysiological states associated with epilepsy. Experimental Approach: Our study models were HEK293T cells heterologously expressing D1 or D5 receptor and CaV3.1-3, and mouse brain slices containing the hippocampus. We used chlorpromazine (D1/D5 inverse agonist) and a D5 receptor mutant lacking constitutive activity as experimental tools. We measured CaV3 currents and excitability parameters using the patch-clamp technique. We completed our study with computational modelling and imaging technique. Key Results: We found a higher sensitivity to TTA-P2 (CaV3 blocker) in CA1 pyramidal neurons obtained from chlorpromazine-treated animals compared with vehicle-treated animals. We found that CaV3.2 and CaV3.3—but not CaV3.1—are targets of D5 receptor constitutive activity in HEK293T cells. Finally, we found an increased firing rate in CA1 pyramidal neurons from chlorpromazine-treated animals in comparison with vehicle-treated animals. Similar changes in firing rate were observed on a neuronal model with controlled CaV3 currents levels. Conclusions and Implications: Native hippocampal CaV3 and recombinant CaV3.2-3 are sensitive to D5 receptor constitutive activity. Manipulation of D5 receptor constitutive activity could be a valuable strategy to control neuronal excitability, especially in exacerbated conditions such as epilepsy.
publishDate 2022
dc.date.none.fl_str_mv 2022-12
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/11336/211497
Mustafá, Emilio Román; Mccarthy, Clara Inés; Portales, Andrea; Cordisco Gonzalez, Santiago; Rodríguez, Silvia Susana; et al.; Constitutive activity of the dopamine (D5) receptor, highly expressed in CA1 hippocampal neurons, selectively reduces CaV3.2 and CaV3.3 currents; Wiley Blackwell Publishing, Inc; British Journal of Pharmacology; 180; 9; 12-2022; 1210-1231
0007-1188
CONICET Digital
CONICET
url http://hdl.handle.net/11336/211497
identifier_str_mv Mustafá, Emilio Román; Mccarthy, Clara Inés; Portales, Andrea; Cordisco Gonzalez, Santiago; Rodríguez, Silvia Susana; et al.; Constitutive activity of the dopamine (D5) receptor, highly expressed in CA1 hippocampal neurons, selectively reduces CaV3.2 and CaV3.3 currents; Wiley Blackwell Publishing, Inc; British Journal of Pharmacology; 180; 9; 12-2022; 1210-1231
0007-1188
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://onlinelibrary.wiley.com/doi/10.1111/bph.16006
info:eu-repo/semantics/altIdentifier/doi/10.1111/bph.16006
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 Blackwell Publishing, Inc
publisher.none.fl_str_mv Wiley Blackwell Publishing, Inc
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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