Gs- versus Golf-dependent functional selectivity mediated by the dopamine D<sub>1</sub> receptor.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 29402888.
- Also identified by DOI 10.1038/s41467-017-02606-w and PMC identifier 5799184.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
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 D<sub>1</sub> 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.
Medical subject headings
- GTP-Binding Protein alpha Subunits
- GTP-Binding Protein alpha Subunits, Gs
- Phenanthridines
- Receptors, Dopamine D1