Genetic Deletion of KLHL1 Leads to Hyperexcitability in Hypothalamic POMC Neurons and Lack of Electrical Responses to Leptin

Autores
Perissinotti, Paula Patricia; Martínez Hernández, Elizabeth; He, Yungui; Koob, Michael D.; Piedras Rentería, Erika S.
Año de publicación
2021
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Kelch-like 1 (KLHL1) is a neuronal actin-binding protein that modulates voltage-gated calcium channels. The KLHL1 knockout (KO) model displays altered calcium channel expression in various brain regions. We analyzed the electrical behavior of hypothalamic POMC (proopiomelanocortin) neurons and their response to leptin. Leptin’s effects on POMC neurons include enhanced gene expression, activation of the ERK1/2 pathway and increased electrical excitability. The latter is initiated by activation of the Jak2-PI3K-PLC pathway, which activates TRPC1/5 (Transient Receptor Potential Cation) channels that in turn recruit T-type channel activity resulting in increased excitability. Here we report over-expression of CaV3.1 T-type channels in the hypothalamus of KLHL1 KO mice increased T-type current density and enhanced POMC neuron basal excitability, rendering them electrically unresponsive to leptin. Electrical sensitivity to leptin was restored by partial blockade of T-type channels. The overexpression of hypothalamic T-type channels in POMC neurons may partially contribute to the obese and abnormal feeding phenotypes observed in KLHL1 KO mice.
Fil: Perissinotti, Paula Patricia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Fisiología, Biología Molecular y Neurociencias. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Fisiología, Biología Molecular y Neurociencias; Argentina
Fil: Martínez Hernández, Elizabeth. Loyola University Of Chicago; Estados Unidos
Fil: He, Yungui. University of Minnesota; Estados Unidos
Fil: Koob, Michael D.. University of Minnesota; Estados Unidos
Fil: Piedras Rentería, Erika S.. Loyola University Of Chicago; Estados Unidos
Materia
CAV3.1
KELCH-LIKE 1
LEPTIN
POMC
T-TYPE CALCIUM CHANNELS
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/175314
Acceder
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network_name_str CONICET Digital (CONICET)
spelling Genetic Deletion of KLHL1 Leads to Hyperexcitability in Hypothalamic POMC Neurons and Lack of Electrical Responses to LeptinPerissinotti, Paula PatriciaMartínez Hernández, ElizabethHe, YunguiKoob, Michael D.Piedras Rentería, Erika S.CAV3.1KELCH-LIKE 1LEPTINPOMCT-TYPE CALCIUM CHANNELShttps://purl.org/becyt/ford/3.1https://purl.org/becyt/ford/3Kelch-like 1 (KLHL1) is a neuronal actin-binding protein that modulates voltage-gated calcium channels. The KLHL1 knockout (KO) model displays altered calcium channel expression in various brain regions. We analyzed the electrical behavior of hypothalamic POMC (proopiomelanocortin) neurons and their response to leptin. Leptin’s effects on POMC neurons include enhanced gene expression, activation of the ERK1/2 pathway and increased electrical excitability. The latter is initiated by activation of the Jak2-PI3K-PLC pathway, which activates TRPC1/5 (Transient Receptor Potential Cation) channels that in turn recruit T-type channel activity resulting in increased excitability. Here we report over-expression of CaV3.1 T-type channels in the hypothalamus of KLHL1 KO mice increased T-type current density and enhanced POMC neuron basal excitability, rendering them electrically unresponsive to leptin. Electrical sensitivity to leptin was restored by partial blockade of T-type channels. The overexpression of hypothalamic T-type channels in POMC neurons may partially contribute to the obese and abnormal feeding phenotypes observed in KLHL1 KO mice.Fil: Perissinotti, Paula Patricia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Fisiología, Biología Molecular y Neurociencias. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Fisiología, Biología Molecular y Neurociencias; ArgentinaFil: Martínez Hernández, Elizabeth. Loyola University Of Chicago; Estados UnidosFil: He, Yungui. University of Minnesota; Estados UnidosFil: Koob, Michael D.. University of Minnesota; Estados UnidosFil: Piedras Rentería, Erika S.. Loyola University Of Chicago; Estados UnidosFrontiers Media2021-09info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/175314Perissinotti, Paula Patricia; Martínez Hernández, Elizabeth; He, Yungui; Koob, Michael D.; Piedras Rentería, Erika S.; Genetic Deletion of KLHL1 Leads to Hyperexcitability in Hypothalamic POMC Neurons and Lack of Electrical Responses to Leptin; Frontiers Media; Frontiers in Neuroscience; 15; 9-2021; 1-161662-453XCONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/doi/10.3389/fnins.2021.718464info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-29T10:46:14Zoai:ri.conicet.gov.ar:11336/175314instacron: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 10:46:15.14CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Genetic Deletion of KLHL1 Leads to Hyperexcitability in Hypothalamic POMC Neurons and Lack of Electrical Responses to Leptin
title Genetic Deletion of KLHL1 Leads to Hyperexcitability in Hypothalamic POMC Neurons and Lack of Electrical Responses to Leptin
spellingShingle Genetic Deletion of KLHL1 Leads to Hyperexcitability in Hypothalamic POMC Neurons and Lack of Electrical Responses to Leptin
Perissinotti, Paula Patricia
CAV3.1
KELCH-LIKE 1
LEPTIN
POMC
T-TYPE CALCIUM CHANNELS
title_short Genetic Deletion of KLHL1 Leads to Hyperexcitability in Hypothalamic POMC Neurons and Lack of Electrical Responses to Leptin
title_full Genetic Deletion of KLHL1 Leads to Hyperexcitability in Hypothalamic POMC Neurons and Lack of Electrical Responses to Leptin
title_fullStr Genetic Deletion of KLHL1 Leads to Hyperexcitability in Hypothalamic POMC Neurons and Lack of Electrical Responses to Leptin
title_full_unstemmed Genetic Deletion of KLHL1 Leads to Hyperexcitability in Hypothalamic POMC Neurons and Lack of Electrical Responses to Leptin
title_sort Genetic Deletion of KLHL1 Leads to Hyperexcitability in Hypothalamic POMC Neurons and Lack of Electrical Responses to Leptin
dc.creator.none.fl_str_mv Perissinotti, Paula Patricia
Martínez Hernández, Elizabeth
He, Yungui
Koob, Michael D.
Piedras Rentería, Erika S.
author Perissinotti, Paula Patricia
author_facet Perissinotti, Paula Patricia
Martínez Hernández, Elizabeth
He, Yungui
Koob, Michael D.
Piedras Rentería, Erika S.
author_role author
author2 Martínez Hernández, Elizabeth
He, Yungui
Koob, Michael D.
Piedras Rentería, Erika S.
author2_role author
author
author
author
dc.subject.none.fl_str_mv CAV3.1
KELCH-LIKE 1
LEPTIN
POMC
T-TYPE CALCIUM CHANNELS
topic CAV3.1
KELCH-LIKE 1
LEPTIN
POMC
T-TYPE CALCIUM CHANNELS
purl_subject.fl_str_mv https://purl.org/becyt/ford/3.1
https://purl.org/becyt/ford/3
dc.description.none.fl_txt_mv Kelch-like 1 (KLHL1) is a neuronal actin-binding protein that modulates voltage-gated calcium channels. The KLHL1 knockout (KO) model displays altered calcium channel expression in various brain regions. We analyzed the electrical behavior of hypothalamic POMC (proopiomelanocortin) neurons and their response to leptin. Leptin’s effects on POMC neurons include enhanced gene expression, activation of the ERK1/2 pathway and increased electrical excitability. The latter is initiated by activation of the Jak2-PI3K-PLC pathway, which activates TRPC1/5 (Transient Receptor Potential Cation) channels that in turn recruit T-type channel activity resulting in increased excitability. Here we report over-expression of CaV3.1 T-type channels in the hypothalamus of KLHL1 KO mice increased T-type current density and enhanced POMC neuron basal excitability, rendering them electrically unresponsive to leptin. Electrical sensitivity to leptin was restored by partial blockade of T-type channels. The overexpression of hypothalamic T-type channels in POMC neurons may partially contribute to the obese and abnormal feeding phenotypes observed in KLHL1 KO mice.
Fil: Perissinotti, Paula Patricia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Fisiología, Biología Molecular y Neurociencias. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Fisiología, Biología Molecular y Neurociencias; Argentina
Fil: Martínez Hernández, Elizabeth. Loyola University Of Chicago; Estados Unidos
Fil: He, Yungui. University of Minnesota; Estados Unidos
Fil: Koob, Michael D.. University of Minnesota; Estados Unidos
Fil: Piedras Rentería, Erika S.. Loyola University Of Chicago; Estados Unidos
description Kelch-like 1 (KLHL1) is a neuronal actin-binding protein that modulates voltage-gated calcium channels. The KLHL1 knockout (KO) model displays altered calcium channel expression in various brain regions. We analyzed the electrical behavior of hypothalamic POMC (proopiomelanocortin) neurons and their response to leptin. Leptin’s effects on POMC neurons include enhanced gene expression, activation of the ERK1/2 pathway and increased electrical excitability. The latter is initiated by activation of the Jak2-PI3K-PLC pathway, which activates TRPC1/5 (Transient Receptor Potential Cation) channels that in turn recruit T-type channel activity resulting in increased excitability. Here we report over-expression of CaV3.1 T-type channels in the hypothalamus of KLHL1 KO mice increased T-type current density and enhanced POMC neuron basal excitability, rendering them electrically unresponsive to leptin. Electrical sensitivity to leptin was restored by partial blockade of T-type channels. The overexpression of hypothalamic T-type channels in POMC neurons may partially contribute to the obese and abnormal feeding phenotypes observed in KLHL1 KO mice.
publishDate 2021
dc.date.none.fl_str_mv 2021-09
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/11336/175314
Perissinotti, Paula Patricia; Martínez Hernández, Elizabeth; He, Yungui; Koob, Michael D.; Piedras Rentería, Erika S.; Genetic Deletion of KLHL1 Leads to Hyperexcitability in Hypothalamic POMC Neurons and Lack of Electrical Responses to Leptin; Frontiers Media; Frontiers in Neuroscience; 15; 9-2021; 1-16
1662-453X
CONICET Digital
CONICET
url http://hdl.handle.net/11336/175314
identifier_str_mv Perissinotti, Paula Patricia; Martínez Hernández, Elizabeth; He, Yungui; Koob, Michael D.; Piedras Rentería, Erika S.; Genetic Deletion of KLHL1 Leads to Hyperexcitability in Hypothalamic POMC Neurons and Lack of Electrical Responses to Leptin; Frontiers Media; Frontiers in Neuroscience; 15; 9-2021; 1-16
1662-453X
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/doi/10.3389/fnins.2021.718464
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv Frontiers Media
publisher.none.fl_str_mv Frontiers Media
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
_version_ 1844614503709278208
score 13.070432

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