Gao is a major determinant of cAMP signaling in the pathophysiology of movement disorders

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Abstract: The G protein alpha subunit o (Gao) is one of the most abundant proteins in the nervous system, and pathogenic mutations in its gene (GNAO1) cause movement disorder. However, the function of Gao is ill defined mechanistically. Here, we show that Gao dictates neuromodulatory responsivenes...

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Autores principales: Muntean, Brian S., Masuho, Ikuo, Dao, Maria, Blakely, Randy D., Grill, Brock, Martemyanov, Kirill A., Sutton, Laurie, Zucca, Stefano, Iwamoto, Hideki, Patil, Dipak N., Wang, Dandan, Birnbaumer, Lutz
Formato: Artículo
Lenguaje:Inglés
Publicado: Elsevier 2021
Materias:
PROTEINAS
CELULAS
FISIOLOGIA
NEUROFISIOLOGIA
QUIMICA CELULAR
Acceso en línea:https://repositorio.uca.edu.ar/handle/123456789/11617
Aporte de:
Repositorio Institucional de la Universidad Católica Argentina (UCA) de Universidad Católica Argentina
id I33-R139-123456789-11617
record_format dspace
spelling I33-R139-123456789-116172023-11-22T21:48:57Z Gao is a major determinant of cAMP signaling in the pathophysiology of movement disorders Muntean, Brian S. Masuho, Ikuo Dao, Maria Blakely, Randy D. Grill, Brock Martemyanov, Kirill A. Sutton, Laurie Zucca, Stefano Iwamoto, Hideki Patil, Dipak N. Wang, Dandan Birnbaumer, Lutz PROTEINAS CELULAS FISIOLOGIA NEUROFISIOLOGIA QUIMICA CELULAR Abstract: The G protein alpha subunit o (Gao) is one of the most abundant proteins in the nervous system, and pathogenic mutations in its gene (GNAO1) cause movement disorder. However, the function of Gao is ill defined mechanistically. Here, we show that Gao dictates neuromodulatory responsiveness of striatal neurons and is required for movement control. Using in vivo optical sensors and enzymatic assays, we determine that Gao provides a separate transduction channel that modulates coupling of both inhibitory and stimulatory dopamine receptors to the cyclic AMP (cAMP)-generating enzyme adenylyl cyclase. Through a combination of cell-based assays and rodent models, we demonstrate that GNAO1-associated mutations alter Gao function in a neuron-type-specific fashion via a combination of a dominant-negative and loss-of-function mechanisms. Overall, our findings suggest thatGao and its pathological variants function in specific circuits to regulate neuromodulatory signals essential for executing motor programs. 2021-06-11T17:53:22Z 2021-06-11T17:53:22Z 2021 Artículo Muntean, B., et al. Gao is a major determinant of cAMP signaling in the pathophysiology of movement disorders [en línea]. Cell Reports. 2021, 34. doi: 10.1016/j.celrep.2021.108718ll. Disponible en: https://repositorio.uca.edu.ar/handle/123456789/11617 2211-1247 (on line) https://repositorio.uca.edu.ar/handle/123456789/11617 10.1016/j.celrep.2021.108718ll 33535037 eng Acceso abierto http://creativecommons.org/licenses/by-nc-sa/4.0/ application/pdf Elsevier Cell Reports. 2021, 34
institution Universidad Católica Argentina
institution_str I-33
repository_str R-139
collection Repositorio Institucional de la Universidad Católica Argentina (UCA)
language Inglés
topic PROTEINAS
CELULAS
FISIOLOGIA
NEUROFISIOLOGIA
QUIMICA CELULAR
spellingShingle PROTEINAS
CELULAS
FISIOLOGIA
NEUROFISIOLOGIA
QUIMICA CELULAR
Muntean, Brian S.
Masuho, Ikuo
Dao, Maria
Blakely, Randy D.
Grill, Brock
Martemyanov, Kirill A.
Sutton, Laurie
Zucca, Stefano
Iwamoto, Hideki
Patil, Dipak N.
Wang, Dandan
Birnbaumer, Lutz
Gao is a major determinant of cAMP signaling in the pathophysiology of movement disorders
topic_facet PROTEINAS
CELULAS
FISIOLOGIA
NEUROFISIOLOGIA
QUIMICA CELULAR
description Abstract: The G protein alpha subunit o (Gao) is one of the most abundant proteins in the nervous system, and pathogenic mutations in its gene (GNAO1) cause movement disorder. However, the function of Gao is ill defined mechanistically. Here, we show that Gao dictates neuromodulatory responsiveness of striatal neurons and is required for movement control. Using in vivo optical sensors and enzymatic assays, we determine that Gao provides a separate transduction channel that modulates coupling of both inhibitory and stimulatory dopamine receptors to the cyclic AMP (cAMP)-generating enzyme adenylyl cyclase. Through a combination of cell-based assays and rodent models, we demonstrate that GNAO1-associated mutations alter Gao function in a neuron-type-specific fashion via a combination of a dominant-negative and loss-of-function mechanisms. Overall, our findings suggest thatGao and its pathological variants function in specific circuits to regulate neuromodulatory signals essential for executing motor programs.
format Artículo
author Muntean, Brian S.
Masuho, Ikuo
Dao, Maria
Blakely, Randy D.
Grill, Brock
Martemyanov, Kirill A.
Sutton, Laurie
Zucca, Stefano
Iwamoto, Hideki
Patil, Dipak N.
Wang, Dandan
Birnbaumer, Lutz
author_facet Muntean, Brian S.
Masuho, Ikuo
Dao, Maria
Blakely, Randy D.
Grill, Brock
Martemyanov, Kirill A.
Sutton, Laurie
Zucca, Stefano
Iwamoto, Hideki
Patil, Dipak N.
Wang, Dandan
Birnbaumer, Lutz
author_sort Muntean, Brian S.
title Gao is a major determinant of cAMP signaling in the pathophysiology of movement disorders
title_short Gao is a major determinant of cAMP signaling in the pathophysiology of movement disorders
title_full Gao is a major determinant of cAMP signaling in the pathophysiology of movement disorders
title_fullStr Gao is a major determinant of cAMP signaling in the pathophysiology of movement disorders
title_full_unstemmed Gao is a major determinant of cAMP signaling in the pathophysiology of movement disorders
title_sort gao is a major determinant of camp signaling in the pathophysiology of movement disorders
publisher Elsevier
publishDate 2021
url https://repositorio.uca.edu.ar/handle/123456789/11617
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