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.

• Authors: 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
• Journal: Cell reports (Cell Rep) Vol. 34 Issue 5 Pg. 108718 (02 02 2021) ISSN: 2211-1247 [Electronic] United States
• PMID: 33535037 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, N.I.H., Intramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.

Chemical References

• Cyclic AMP
• GTP-Binding Protein alpha Subunits, Gi-Go

Topics

• Animals
• Cyclic AMP (metabolism)
• GTP-Binding Protein alpha Subunits, Gi-Go (metabolism)
• Humans
• Mice
• Movement Disorders (genetics)