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

Area of Science:

• Neuroscience
• Molecular Pharmacology
• G protein-coupled receptors

Background:

• Gαs (Gs) and Gαolf (Golf) are homologous stimulatory G proteins with distinct brain expression patterns: Gs in the cortex and Golf in the striatum.
• The dopamine D1 receptor (D1R) interacts with both Gs and Golf, and its dysregulation is implicated in neuropsychiatric disorders, making it a key therapeutic target.

Purpose of the Study:

• To investigate the functional distinctions between Gs and Golf coupling with the dopamine D1 receptor (D1R).
• To explore the potential for Gs/Golf-dependent biased agonism in developing targeted therapeutics for neuropsychiatric conditions.

Main Methods:

• Utilized novel drug screening assays to analyze specific G-protein subtype coupling to the D1R.
• Evaluated ligand efficacy (full vs. partial agonism) for D1R when coupled to Gs versus Golf.

Main Results:

• Dihydrexidine and N-propyl-apomorphine exhibited biased agonism at the D1R, acting as full agonists with Gs but partial agonists with Golf.
• This Gs/Golf-dependent functional selectivity was confirmed across cellular signaling, neuronal function, and behavioral analyses.

Conclusions:

• The findings demonstrate Gs/Golf-dependent functional selectivity in D1R ligands.
• This discovery opens new therapeutic avenues for neuropsychiatric disorders by targeting cortex-specific or striatum-specific dysfunctions.