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

The G protein alpha subunit o (G alpha o) 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 G alpha o is ill defined mechanistically. Here, we show that G alpha o dictates neuromodulatory responsiveness of striatal neurons and is required for movement control. Using in vivo optical sensors and enzymatic assays, we determine that G alpha o 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 G alpha o function in a neuron-type-specific fashion via a combination of a dominant-negative and loss-of-function mechanisms. Overall, our findings suggest that G alpha o and its pathological variants function in specific circuits to regulate neuromodulatory signals essential for executing motor programs.

Automated summary

The study demonstrates that G protein alpha subunit o plays a crucial role in the nervous system by modulating neuromodulatory signals in striatal neurons, essential for motor control. Pathogenic mutations in its gene are shown to alter G alpha o function in a neuron-type specific manner, affecting movement disorders.