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

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

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

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.

Original languageEnglish (US)
Article number108718
JournalCell Reports
Volume34
Issue number5
DOIs
StatePublished - Feb 2 2021
Externally publishedYes

Keywords

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

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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