@article{3b6acc38ded84d098e6c571b09579463,
title = "Gαo is a major determinant of cAMP signaling in the pathophysiology of movement disorders",
abstract = "The G protein alpha subunit o (Gαo) 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 Gαo is ill defined mechanistically. Here, we show that Gαo dictates neuromodulatory responsiveness of striatal neurons and is required for movement control. Using in vivo optical sensors and enzymatic assays, we determine that Gαo 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 Gαo function in a neuron-type-specific fashion via a combination of a dominant-negative and loss-of-function mechanisms. Overall, our findings suggest that Gαo and its pathological variants function in specific circuits to regulate neuromodulatory signals essential for executing motor programs.",
keywords = "GPCR, Gαo, cAMP, disease mechanisms, heterotrimeric G proteins, movement disorder, mutations, neuromodulation, striatum, synaptic plasticity",
author = "Muntean, {Brian S.} and Ikuo Masuho and Maria Dao and Sutton, {Laurie P.} and Stefano Zucca and Hideki Iwamoto and Patil, {Dipak N.} and Dandan Wang and Lutz Birnbaumer and Blakely, {Randy D.} and Brock Grill and Martemyanov, {Kirill A.}",
note = "Funding Information: We thank Natalia Martemyanova for husbandry, maintenance, and genotyping of all the mice examined in this study, as well as Nickolas K. Skamangas and Hideko Masuho for technical support. This work was supported by funding from the NIH (grants DA041207 to B.S.M. DA048579 to S.Z. NS072129 to B.G. and DA036596 and DA026405 to K.A.M.) and the Intramural Research Program of the NIH (project Z01-ES-101643 to L.B.). This work was also supported by a research fellowship from the Bow Foundation (B.S.M.). B.S.M. designed and performed all imaging experiments, analyzed the data, and wrote the paper; L.P.S. and M.D. designed and performed all behavioral experiments and analyzed the data; I.M. designed and performed the experiments analyzing effects of clinical mutations in cell-based assays and analyzed the data; S.Z. designed and performed all electrophysiological experiments and analyzed the data; D.W. and B.G. were involved in analysis of mutation mechanisms; D.N.P. generated critical reagent (recombinant proteins); L.B. generated critical reagent (Gnao1flx mice); B.G. and R.D.B. participated in writing the manuscript; H.I. performed voltammetry studies; K.A.M. conceived the study, designed experiments, analyzed the data, and wrote the paper with feedback from all authors; and all authors participated in editing the manuscript. The authors declare no competing interests. Funding Information: We thank Natalia Martemyanova for husbandry, maintenance, and genotyping of all the mice examined in this study, as well as Nickolas K. Skamangas and Hideko Masuho for technical support. This work was supported by funding from the NIH (grants DA041207 to B.S.M., DA048579 to S.Z., NS072129 to B.G., and DA036596 and DA026405 to K.A.M.) and the Intramural Research Program of the NIH (project Z01-ES-101643 to L.B.). This work was also supported by a research fellowship from the Bow Foundation (B.S.M.). Publisher Copyright: {\textcopyright} 2021 The Author(s)",
year = "2021",
month = feb,
day = "2",
doi = "10.1016/j.celrep.2021.108718",
language = "English (US)",
volume = "34",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "5",
}