Gain-of-function mutations in the UNC-2/CaV2α channel lead to excitation-dominant synaptic transmission in C. elegans

Autores
Huang, Yung Chi; Pirri, Jennifer K.; Rayes, Diego Hernán; Gao, Shangbang; Mulcahy, Ben; Grant, Jeff; Saheki, Yasunori; Francis, Michael M.; Zhen, Mei; Alkema, Mark J.
Año de publicación
2019
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Mutations in pre-synaptic voltage gated calcium channels can lead to familial hemiplegic migraine type 1 (FHM1). While mammalian studies indicate that the migraine brain is hyperexcitable due to enhanced excitation or reduced inhibition, the molecular and cellular mechanisms underlying this excitatory/inhibitory (E/I) imbalance are poorly understood. We identified a gain-of-function (gf) mutation in the Caenorhabditis elegans CaV2 channel α1 subunit, UNC-2, which leads to increased calcium currents. unc-2(zf35gf) mutants exhibit hyperactivity and seizure-like motor behaviors. Expression of the unc-2 gene with FHM1 substitutions R192Q and S218L leads to hyperactivity similar to that of unc-2(zf35gf) mutants. unc-2(zf35gf) mutants display increased cholinergic-and decreased GABAergic-transmission. Moreover, increased cholinergic transmission in unc-2(zf35gf) mutants leads to an increase of cholinergic synapses and a TAX-6/calcineurin dependent reduction of GABA synapses. Our studies reveal mechanisms through which CaV2 gain-of-function mutations disrupt excitation-inhibition balance in the nervous system.
Fil: Huang, Yung Chi. University of Massachussets; Estados Unidos
Fil: Pirri, Jennifer K.. University of Massachussets; Estados Unidos
Fil: Rayes, Diego Hernán. University of Massachussets; Estados Unidos. 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: Gao, Shangbang. Mount Sinai Hospital; Estados Unidos
Fil: Mulcahy, Ben. Mount Sinai Hospital; Estados Unidos
Fil: Grant, Jeff. University of Massachussets; Estados Unidos
Fil: Saheki, Yasunori. The Rockefeller University; Estados Unidos
Fil: Francis, Michael M.. University of Massachussets; Estados Unidos
Fil: Zhen, Mei. University of Toronto; Canadá. Mount Sinai Hospital; Estados Unidos
Fil: Alkema, Mark J.. University of Massachussets; Estados Unidos
Materia
CaV2
C. elegans
Hyperactivity
Gain of function
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:11336/99040
Acceder
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oai_identifier_str oai:ri.conicet.gov.ar:11336/99040
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Gain-of-function mutations in the UNC-2/CaV2α channel lead to excitation-dominant synaptic transmission in C. elegansHuang, Yung ChiPirri, Jennifer K.Rayes, Diego HernánGao, ShangbangMulcahy, BenGrant, JeffSaheki, YasunoriFrancis, Michael M.Zhen, MeiAlkema, Mark J.CaV2C. elegansHyperactivityGain of functionhttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1Mutations in pre-synaptic voltage gated calcium channels can lead to familial hemiplegic migraine type 1 (FHM1). While mammalian studies indicate that the migraine brain is hyperexcitable due to enhanced excitation or reduced inhibition, the molecular and cellular mechanisms underlying this excitatory/inhibitory (E/I) imbalance are poorly understood. We identified a gain-of-function (gf) mutation in the Caenorhabditis elegans CaV2 channel α1 subunit, UNC-2, which leads to increased calcium currents. unc-2(zf35gf) mutants exhibit hyperactivity and seizure-like motor behaviors. Expression of the unc-2 gene with FHM1 substitutions R192Q and S218L leads to hyperactivity similar to that of unc-2(zf35gf) mutants. unc-2(zf35gf) mutants display increased cholinergic-and decreased GABAergic-transmission. Moreover, increased cholinergic transmission in unc-2(zf35gf) mutants leads to an increase of cholinergic synapses and a TAX-6/calcineurin dependent reduction of GABA synapses. Our studies reveal mechanisms through which CaV2 gain-of-function mutations disrupt excitation-inhibition balance in the nervous system.Fil: Huang, Yung Chi. University of Massachussets; Estados UnidosFil: Pirri, Jennifer K.. University of Massachussets; Estados UnidosFil: Rayes, Diego Hernán. University of Massachussets; Estados Unidos. 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: Gao, Shangbang. Mount Sinai Hospital; Estados UnidosFil: Mulcahy, Ben. Mount Sinai Hospital; Estados UnidosFil: Grant, Jeff. University of Massachussets; Estados UnidosFil: Saheki, Yasunori. The Rockefeller University; Estados UnidosFil: Francis, Michael M.. University of Massachussets; Estados UnidosFil: Zhen, Mei. University of Toronto; Canadá. Mount Sinai Hospital; Estados UnidosFil: Alkema, Mark J.. University of Massachussets; Estados UnidoseLife Sciences Publications Ltd2019-08-05info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/99040Huang, Yung Chi; Pirri, Jennifer K.; Rayes, Diego Hernán; Gao, Shangbang; Mulcahy, Ben; et al.; Gain-of-function mutations in the UNC-2/CaV2α channel lead to excitation-dominant synaptic transmission in C. elegans; eLife Sciences Publications Ltd; eLife; 8; 05-8-2019; 1-282050-084XCONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://elifesciences.org/articles/45905info:eu-repo/semantics/altIdentifier/doi/10.7554/eLife.45905info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-29T09:34:08Zoai:ri.conicet.gov.ar:11336/99040instacron: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 09:34:09.025CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Gain-of-function mutations in the UNC-2/CaV2α channel lead to excitation-dominant synaptic transmission in C. elegans
title Gain-of-function mutations in the UNC-2/CaV2α channel lead to excitation-dominant synaptic transmission in C. elegans
spellingShingle Gain-of-function mutations in the UNC-2/CaV2α channel lead to excitation-dominant synaptic transmission in C. elegans
Huang, Yung Chi
CaV2
C. elegans
Hyperactivity
Gain of function
title_short Gain-of-function mutations in the UNC-2/CaV2α channel lead to excitation-dominant synaptic transmission in C. elegans
title_full Gain-of-function mutations in the UNC-2/CaV2α channel lead to excitation-dominant synaptic transmission in C. elegans
title_fullStr Gain-of-function mutations in the UNC-2/CaV2α channel lead to excitation-dominant synaptic transmission in C. elegans
title_full_unstemmed Gain-of-function mutations in the UNC-2/CaV2α channel lead to excitation-dominant synaptic transmission in C. elegans
title_sort Gain-of-function mutations in the UNC-2/CaV2α channel lead to excitation-dominant synaptic transmission in C. elegans
dc.creator.none.fl_str_mv Huang, Yung Chi
Pirri, Jennifer K.
Rayes, Diego Hernán
Gao, Shangbang
Mulcahy, Ben
Grant, Jeff
Saheki, Yasunori
Francis, Michael M.
Zhen, Mei
Alkema, Mark J.
author Huang, Yung Chi
author_facet Huang, Yung Chi
Pirri, Jennifer K.
Rayes, Diego Hernán
Gao, Shangbang
Mulcahy, Ben
Grant, Jeff
Saheki, Yasunori
Francis, Michael M.
Zhen, Mei
Alkema, Mark J.
author_role author
author2 Pirri, Jennifer K.
Rayes, Diego Hernán
Gao, Shangbang
Mulcahy, Ben
Grant, Jeff
Saheki, Yasunori
Francis, Michael M.
Zhen, Mei
Alkema, Mark J.
author2_role author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv CaV2
C. elegans
Hyperactivity
Gain of function
topic CaV2
C. elegans
Hyperactivity
Gain of function
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.6
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv Mutations in pre-synaptic voltage gated calcium channels can lead to familial hemiplegic migraine type 1 (FHM1). While mammalian studies indicate that the migraine brain is hyperexcitable due to enhanced excitation or reduced inhibition, the molecular and cellular mechanisms underlying this excitatory/inhibitory (E/I) imbalance are poorly understood. We identified a gain-of-function (gf) mutation in the Caenorhabditis elegans CaV2 channel α1 subunit, UNC-2, which leads to increased calcium currents. unc-2(zf35gf) mutants exhibit hyperactivity and seizure-like motor behaviors. Expression of the unc-2 gene with FHM1 substitutions R192Q and S218L leads to hyperactivity similar to that of unc-2(zf35gf) mutants. unc-2(zf35gf) mutants display increased cholinergic-and decreased GABAergic-transmission. Moreover, increased cholinergic transmission in unc-2(zf35gf) mutants leads to an increase of cholinergic synapses and a TAX-6/calcineurin dependent reduction of GABA synapses. Our studies reveal mechanisms through which CaV2 gain-of-function mutations disrupt excitation-inhibition balance in the nervous system.
Fil: Huang, Yung Chi. University of Massachussets; Estados Unidos
Fil: Pirri, Jennifer K.. University of Massachussets; Estados Unidos
Fil: Rayes, Diego Hernán. University of Massachussets; Estados Unidos. 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: Gao, Shangbang. Mount Sinai Hospital; Estados Unidos
Fil: Mulcahy, Ben. Mount Sinai Hospital; Estados Unidos
Fil: Grant, Jeff. University of Massachussets; Estados Unidos
Fil: Saheki, Yasunori. The Rockefeller University; Estados Unidos
Fil: Francis, Michael M.. University of Massachussets; Estados Unidos
Fil: Zhen, Mei. University of Toronto; Canadá. Mount Sinai Hospital; Estados Unidos
Fil: Alkema, Mark J.. University of Massachussets; Estados Unidos
description Mutations in pre-synaptic voltage gated calcium channels can lead to familial hemiplegic migraine type 1 (FHM1). While mammalian studies indicate that the migraine brain is hyperexcitable due to enhanced excitation or reduced inhibition, the molecular and cellular mechanisms underlying this excitatory/inhibitory (E/I) imbalance are poorly understood. We identified a gain-of-function (gf) mutation in the Caenorhabditis elegans CaV2 channel α1 subunit, UNC-2, which leads to increased calcium currents. unc-2(zf35gf) mutants exhibit hyperactivity and seizure-like motor behaviors. Expression of the unc-2 gene with FHM1 substitutions R192Q and S218L leads to hyperactivity similar to that of unc-2(zf35gf) mutants. unc-2(zf35gf) mutants display increased cholinergic-and decreased GABAergic-transmission. Moreover, increased cholinergic transmission in unc-2(zf35gf) mutants leads to an increase of cholinergic synapses and a TAX-6/calcineurin dependent reduction of GABA synapses. Our studies reveal mechanisms through which CaV2 gain-of-function mutations disrupt excitation-inhibition balance in the nervous system.
publishDate 2019
dc.date.none.fl_str_mv 2019-08-05
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/11336/99040
Huang, Yung Chi; Pirri, Jennifer K.; Rayes, Diego Hernán; Gao, Shangbang; Mulcahy, Ben; et al.; Gain-of-function mutations in the UNC-2/CaV2α channel lead to excitation-dominant synaptic transmission in C. elegans; eLife Sciences Publications Ltd; eLife; 8; 05-8-2019; 1-28
2050-084X
CONICET Digital
CONICET
url http://hdl.handle.net/11336/99040
identifier_str_mv Huang, Yung Chi; Pirri, Jennifer K.; Rayes, Diego Hernán; Gao, Shangbang; Mulcahy, Ben; et al.; Gain-of-function mutations in the UNC-2/CaV2α channel lead to excitation-dominant synaptic transmission in C. elegans; eLife Sciences Publications Ltd; eLife; 8; 05-8-2019; 1-28
2050-084X
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://elifesciences.org/articles/45905
info:eu-repo/semantics/altIdentifier/doi/10.7554/eLife.45905
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 eLife Sciences Publications Ltd
publisher.none.fl_str_mv eLife Sciences Publications Ltd
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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