| First Author | Muntean BS | Year | 2021 |
| Journal | Cell Rep | Volume | 34 |
| Issue | 5 | Pages | 108718 |
| PubMed ID | 33535037 | Mgi Jnum | J:304278 |
| Mgi Id | MGI:6694815 | Doi | 10.1016/j.celrep.2021.108718 |
| Citation | Muntean BS, et al. (2021) Galphao is a major determinant of cAMP signaling in the pathophysiology of movement disorders. Cell Rep 34(5):108718 |
| abstractText | The G protein alpha subunit o (Galphao) 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 Galphao is ill defined mechanistically. Here, we show that Galphao dictates neuromodulatory responsiveness of striatal neurons and is required for movement control. Using in vivo optical sensors and enzymatic assays, we determine that Galphao 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 Galphao function in a neuron-type-specific fashion via a combination of a dominant-negative and loss-of-function mechanisms. Overall, our findings suggest that Galphao and its pathological variants function in specific circuits to regulate neuromodulatory signals essential for executing motor programs. |
