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

Abstract

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.