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

Hideaki Yano (), Ning-Sheng Cai, Min Xu, Ravi Kumar Verma, William Rea, Alexander F. Hoffman, Lei Shi, Jonathan A. Javitch, Antonello Bonci and Sergi Ferré
Additional contact information
Hideaki Yano: National Institutes of Health
Ning-Sheng Cai: National Institutes of Health
Min Xu: National Institutes of Health
Ravi Kumar Verma: National Institutes of Health
William Rea: National Institutes of Health
Alexander F. Hoffman: National Institutes of Health
Lei Shi: National Institutes of Health
Jonathan A. Javitch: Columbia University
Antonello Bonci: National Institutes of Health
Sergi Ferré: National Institutes of Health

Nature Communications, 2018, vol. 9, issue 1, 1-11

Abstract: Abstract 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 D1 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.

Date: 2018
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DOI: 10.1038/s41467-017-02606-w

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