CB1R activates the epilepsy-associated protein Go to regulate neurotransmitter release and synaptic plasticity in the cerebellum

Autores
Choi, Jung-Mi; Acharya, Rakshya; Cha, Hye Lim; Lee, Kwang-Wook; Seo, Jewoo; Yang, Esther; Kim, Hyun; Yoon, Jong Hyuk; Chang, Da-Young; Kim, Sung-Soo; Kim, Sang Jeong; Birnbaumer, Lutz; Suh-Kim, Haeyoung
Año de publicación
2024
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
GNAO1 encodes the alpha subunit of the heterotrimeric Go protein. Despite being the most abundant G protein at synapses, the role of Go in the brain remains unclear, primarily because of the high mortality associated with developmental and epileptic encephalopathy (DEE) 17 in Gnao1 mutated animals. Here, we conducted proteomic analyses with a brain synaptosomal fraction to investigate the Go-interactome and then generated a non-DEE model using Gli1CreERT2 mice to selectively knockout (KO) the presynaptic Gαo within cerebellum. Our findings revealed that Gαo interacts with multiple proteins involved in neurotransmitter release, as well as cannabinoid receptor type 1 (CB1R), a key Gi/o-coupled receptor in presynaptic terminals. In Gnao1 KO mice, synapse formation was reduced in the cerebellum with a concomitant reduction in depolarization-induced suppression of excitation, a manifestation of CB1R-mediated synaptic plasticity found in the cerebellum. These mice displayed motor deficits in rotarod, grip strength, gait, and beam balance tests. Our results suggest that Go plays a critical role in regulating neurotransmitter releases at the presynaptic terminals and its absence in the entire brain may contribute to DEE pathogenesis. This study also provides valuable insights into the signaling pathways in the brain from a Go-dependent perspective.
Fil: Choi, Jung-Mi. Seoul National University College Of Medicine; Corea del Sur
Fil: Acharya, Rakshya. Seoul National University College Of Medicine; Corea del Sur
Fil: Cha, Hye Lim. Ajou University School of Medicine; Corea del Sur
Fil: Lee, Kwang-Wook. Ajou University School of Medicine; Corea del Sur
Fil: Seo, Jewoo. Seoul National University College Of Medicine; Corea del Sur
Fil: Yang, Esther. Korea University; Corea del Norte
Fil: Kim, Hyun. Korea Brain Research Institute; Corea del Sur
Fil: Yoon, Jong Hyuk. Korea Brain Research Institute; Corea del Sur
Fil: Chang, Da-Young. No especifíca;
Fil: Kim, Sung-Soo. Ajou University School of Medicine; Corea del Sur
Fil: Kim, Sang Jeong. Seoul National University College Of Medicine; Corea del Sur
Fil: Birnbaumer, Lutz. Pontificia Universidad Católica Argentina "Santa María de los Buenos Aires". Instituto de Investigaciones Biomédicas. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas; Argentina
Fil: Suh-Kim, Haeyoung. Ajou University School of Medicine; Corea del Sur
Materia
CB1R
CEREBELLUM
GNAO1
G PROTEIN
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:11336/278796
Acceder
id CONICETDig_878e6bbef654153fe40861824483e519
oai_identifier_str oai:ri.conicet.gov.ar:11336/278796
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling CB1R activates the epilepsy-associated protein Go to regulate neurotransmitter release and synaptic plasticity in the cerebellumChoi, Jung-MiAcharya, RakshyaCha, Hye LimLee, Kwang-WookSeo, JewooYang, EstherKim, HyunYoon, Jong HyukChang, Da-YoungKim, Sung-SooKim, Sang JeongBirnbaumer, LutzSuh-Kim, HaeyoungCB1RCEREBELLUMGNAO1G PROTEINhttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1GNAO1 encodes the alpha subunit of the heterotrimeric Go protein. Despite being the most abundant G protein at synapses, the role of Go in the brain remains unclear, primarily because of the high mortality associated with developmental and epileptic encephalopathy (DEE) 17 in Gnao1 mutated animals. Here, we conducted proteomic analyses with a brain synaptosomal fraction to investigate the Go-interactome and then generated a non-DEE model using Gli1CreERT2 mice to selectively knockout (KO) the presynaptic Gαo within cerebellum. Our findings revealed that Gαo interacts with multiple proteins involved in neurotransmitter release, as well as cannabinoid receptor type 1 (CB1R), a key Gi/o-coupled receptor in presynaptic terminals. In Gnao1 KO mice, synapse formation was reduced in the cerebellum with a concomitant reduction in depolarization-induced suppression of excitation, a manifestation of CB1R-mediated synaptic plasticity found in the cerebellum. These mice displayed motor deficits in rotarod, grip strength, gait, and beam balance tests. Our results suggest that Go plays a critical role in regulating neurotransmitter releases at the presynaptic terminals and its absence in the entire brain may contribute to DEE pathogenesis. This study also provides valuable insights into the signaling pathways in the brain from a Go-dependent perspective.Fil: Choi, Jung-Mi. Seoul National University College Of Medicine; Corea del SurFil: Acharya, Rakshya. Seoul National University College Of Medicine; Corea del SurFil: Cha, Hye Lim. Ajou University School of Medicine; Corea del SurFil: Lee, Kwang-Wook. Ajou University School of Medicine; Corea del SurFil: Seo, Jewoo. Seoul National University College Of Medicine; Corea del SurFil: Yang, Esther. Korea University; Corea del NorteFil: Kim, Hyun. Korea Brain Research Institute; Corea del SurFil: Yoon, Jong Hyuk. Korea Brain Research Institute; Corea del SurFil: Chang, Da-Young. No especifíca;Fil: Kim, Sung-Soo. Ajou University School of Medicine; Corea del SurFil: Kim, Sang Jeong. Seoul National University College Of Medicine; Corea del SurFil: Birnbaumer, Lutz. Pontificia Universidad Católica Argentina "Santa María de los Buenos Aires". Instituto de Investigaciones Biomédicas. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas; ArgentinaFil: Suh-Kim, Haeyoung. Ajou University School of Medicine; Corea del SurNational Academy of Sciences2024-11info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/278796Choi, Jung-Mi; Acharya, Rakshya; Cha, Hye Lim; Lee, Kwang-Wook; Seo, Jewoo; et al.; CB1R activates the epilepsy-associated protein Go to regulate neurotransmitter release and synaptic plasticity in the cerebellum; National Academy of Sciences; Proceedings of the National Academy of Sciences of The United States of America; 121; 49; 11-2024; 1-100027-8424CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://pnas.org/doi/10.1073/pnas.2409773121info:eu-repo/semantics/altIdentifier/doi/10.1073/pnas.2409773121info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2026-02-06T12:24:13Zoai:ri.conicet.gov.ar:11336/278796instacron: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:34982026-02-06 12:24:14.147CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv CB1R activates the epilepsy-associated protein Go to regulate neurotransmitter release and synaptic plasticity in the cerebellum
title CB1R activates the epilepsy-associated protein Go to regulate neurotransmitter release and synaptic plasticity in the cerebellum
spellingShingle CB1R activates the epilepsy-associated protein Go to regulate neurotransmitter release and synaptic plasticity in the cerebellum
Choi, Jung-Mi
CB1R
CEREBELLUM
GNAO1
G PROTEIN
title_short CB1R activates the epilepsy-associated protein Go to regulate neurotransmitter release and synaptic plasticity in the cerebellum
title_full CB1R activates the epilepsy-associated protein Go to regulate neurotransmitter release and synaptic plasticity in the cerebellum
title_fullStr CB1R activates the epilepsy-associated protein Go to regulate neurotransmitter release and synaptic plasticity in the cerebellum
title_full_unstemmed CB1R activates the epilepsy-associated protein Go to regulate neurotransmitter release and synaptic plasticity in the cerebellum
title_sort CB1R activates the epilepsy-associated protein Go to regulate neurotransmitter release and synaptic plasticity in the cerebellum
dc.creator.none.fl_str_mv Choi, Jung-Mi
Acharya, Rakshya
Cha, Hye Lim
Lee, Kwang-Wook
Seo, Jewoo
Yang, Esther
Kim, Hyun
Yoon, Jong Hyuk
Chang, Da-Young
Kim, Sung-Soo
Kim, Sang Jeong
Birnbaumer, Lutz
Suh-Kim, Haeyoung
author Choi, Jung-Mi
author_facet Choi, Jung-Mi
Acharya, Rakshya
Cha, Hye Lim
Lee, Kwang-Wook
Seo, Jewoo
Yang, Esther
Kim, Hyun
Yoon, Jong Hyuk
Chang, Da-Young
Kim, Sung-Soo
Kim, Sang Jeong
Birnbaumer, Lutz
Suh-Kim, Haeyoung
author_role author
author2 Acharya, Rakshya
Cha, Hye Lim
Lee, Kwang-Wook
Seo, Jewoo
Yang, Esther
Kim, Hyun
Yoon, Jong Hyuk
Chang, Da-Young
Kim, Sung-Soo
Kim, Sang Jeong
Birnbaumer, Lutz
Suh-Kim, Haeyoung
author2_role author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv CB1R
CEREBELLUM
GNAO1
G PROTEIN
topic CB1R
CEREBELLUM
GNAO1
G PROTEIN
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.6
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv GNAO1 encodes the alpha subunit of the heterotrimeric Go protein. Despite being the most abundant G protein at synapses, the role of Go in the brain remains unclear, primarily because of the high mortality associated with developmental and epileptic encephalopathy (DEE) 17 in Gnao1 mutated animals. Here, we conducted proteomic analyses with a brain synaptosomal fraction to investigate the Go-interactome and then generated a non-DEE model using Gli1CreERT2 mice to selectively knockout (KO) the presynaptic Gαo within cerebellum. Our findings revealed that Gαo interacts with multiple proteins involved in neurotransmitter release, as well as cannabinoid receptor type 1 (CB1R), a key Gi/o-coupled receptor in presynaptic terminals. In Gnao1 KO mice, synapse formation was reduced in the cerebellum with a concomitant reduction in depolarization-induced suppression of excitation, a manifestation of CB1R-mediated synaptic plasticity found in the cerebellum. These mice displayed motor deficits in rotarod, grip strength, gait, and beam balance tests. Our results suggest that Go plays a critical role in regulating neurotransmitter releases at the presynaptic terminals and its absence in the entire brain may contribute to DEE pathogenesis. This study also provides valuable insights into the signaling pathways in the brain from a Go-dependent perspective.
Fil: Choi, Jung-Mi. Seoul National University College Of Medicine; Corea del Sur
Fil: Acharya, Rakshya. Seoul National University College Of Medicine; Corea del Sur
Fil: Cha, Hye Lim. Ajou University School of Medicine; Corea del Sur
Fil: Lee, Kwang-Wook. Ajou University School of Medicine; Corea del Sur
Fil: Seo, Jewoo. Seoul National University College Of Medicine; Corea del Sur
Fil: Yang, Esther. Korea University; Corea del Norte
Fil: Kim, Hyun. Korea Brain Research Institute; Corea del Sur
Fil: Yoon, Jong Hyuk. Korea Brain Research Institute; Corea del Sur
Fil: Chang, Da-Young. No especifíca;
Fil: Kim, Sung-Soo. Ajou University School of Medicine; Corea del Sur
Fil: Kim, Sang Jeong. Seoul National University College Of Medicine; Corea del Sur
Fil: Birnbaumer, Lutz. Pontificia Universidad Católica Argentina "Santa María de los Buenos Aires". Instituto de Investigaciones Biomédicas. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas; Argentina
Fil: Suh-Kim, Haeyoung. Ajou University School of Medicine; Corea del Sur
description GNAO1 encodes the alpha subunit of the heterotrimeric Go protein. Despite being the most abundant G protein at synapses, the role of Go in the brain remains unclear, primarily because of the high mortality associated with developmental and epileptic encephalopathy (DEE) 17 in Gnao1 mutated animals. Here, we conducted proteomic analyses with a brain synaptosomal fraction to investigate the Go-interactome and then generated a non-DEE model using Gli1CreERT2 mice to selectively knockout (KO) the presynaptic Gαo within cerebellum. Our findings revealed that Gαo interacts with multiple proteins involved in neurotransmitter release, as well as cannabinoid receptor type 1 (CB1R), a key Gi/o-coupled receptor in presynaptic terminals. In Gnao1 KO mice, synapse formation was reduced in the cerebellum with a concomitant reduction in depolarization-induced suppression of excitation, a manifestation of CB1R-mediated synaptic plasticity found in the cerebellum. These mice displayed motor deficits in rotarod, grip strength, gait, and beam balance tests. Our results suggest that Go plays a critical role in regulating neurotransmitter releases at the presynaptic terminals and its absence in the entire brain may contribute to DEE pathogenesis. This study also provides valuable insights into the signaling pathways in the brain from a Go-dependent perspective.
publishDate 2024
dc.date.none.fl_str_mv 2024-11
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/11336/278796
Choi, Jung-Mi; Acharya, Rakshya; Cha, Hye Lim; Lee, Kwang-Wook; Seo, Jewoo; et al.; CB1R activates the epilepsy-associated protein Go to regulate neurotransmitter release and synaptic plasticity in the cerebellum; National Academy of Sciences; Proceedings of the National Academy of Sciences of The United States of America; 121; 49; 11-2024; 1-10
0027-8424
CONICET Digital
CONICET
url http://hdl.handle.net/11336/278796
identifier_str_mv Choi, Jung-Mi; Acharya, Rakshya; Cha, Hye Lim; Lee, Kwang-Wook; Seo, Jewoo; et al.; CB1R activates the epilepsy-associated protein Go to regulate neurotransmitter release and synaptic plasticity in the cerebellum; National Academy of Sciences; Proceedings of the National Academy of Sciences of The United States of America; 121; 49; 11-2024; 1-10
0027-8424
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://pnas.org/doi/10.1073/pnas.2409773121
info:eu-repo/semantics/altIdentifier/doi/10.1073/pnas.2409773121
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
dc.publisher.none.fl_str_mv National Academy of Sciences
publisher.none.fl_str_mv National Academy of Sciences
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_ 1856403045436358656
score 13.11174

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