Gs- versus Golf-dependent functional selectivity mediated by the dopamine D1 receptor

• Published in: Nature communications Vol. 9; no. 1; pp. 1 - 11
• Main Authors: Yano, Hideaki, Cai, Ning-Sheng, Xu, Min, Verma, Ravi Kumar, Rea, William, Hoffman, Alexander F., Shi, Lei, Javitch, Jonathan A., Bonci, Antonello, Ferré, Sergi
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 05-02-2018; Nature Publishing Group; Nature Portfolio
• Subjects: 631/378/340; 631/92/436/2387; 64; 64/110; 9/10; 9/74; Apomorphine; Brain; Cortex; Dopamine; Dopamine D1 receptors; Drug screening; Homology; Humanities and Social Sciences; Mental disorders; multidisciplinary; Neostriatum; Proteins; Science; Science (multidisciplinary); Selectivity; Signaling
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-017-02606-w

The two highly homologous subtypes of stimulatory G proteins Gαs (Gs) and Gαolf (Golf) display contrasting expression patterns in the brain. Golf is predominant in the striatum, while Gs is predominant in the cortex. Yet, little is known about their functional distinctions. The dopamine D
1
receptor (D1R) couples to Gs/olf and is highly expressed in cortical and striatal areas, making it an important therapeutic target for neuropsychiatric disorders. Using novel drug screening methods that allow analysis of specific G-protein subtype coupling, we found that, relative to dopamine, dihydrexidine and N-propyl-apomorphine behave as full D1R agonists when coupled to Gs, but as partial D1R agonists when coupled to Golf. The Gs/Golf-dependent biased agonism by dihydrexidine was consistently observed at the levels of cellular signaling, neuronal function, and behavior. Our findings of Gs/Golf-dependent functional selectivity in D1R ligands open a new avenue for the treatment of cortex-specific or striatum-specific neuropsychiatric dysfunction.
D1-like dopamine receptors are coupled to Golf proteins in the dorsal striatum but Gs in cortical and other areas. Here, the authors demonstrate selective agonism of Gs-coupled versus Golf-coupled D1 receptors.