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

Cell Rep. 2021-02; 
Brian S Muntean, Ikuo Masuho, Maria Dao, Laurie P Sutton, Stefano Zucca, Hideki Iwamoto, Dipak N Patil, Dandan Wang, Lutz Birnbaumer, Randy D Blakely, Brock Grill, Kirill A Martemyanov
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摘要

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 alte... More

关键词

GPCR, Gαo, cAMP, disease mechanisms, heterotrimeric G proteins, movement disorder, mutations, neuromodulation, striatum, synaptic plasticity