University of Southern California-led researchers have discovered the structural details of a brain receptor called GPR6, which could lead to new treatments for Parkinson's disease.

GPR6 is an orphan G protein-coupled receptor primarily expressed in the central nervous system. It is highly enriched in dopamine D2 receptor–expressing spiny neurons within a striatopallidal pathway that becomes hyperactive in Parkinson's disease.

Parkinson's disease is characterised by the degeneration of dopamine-producing neurons in the substantia nigra pars compacta, a specific region of the brain, leading to dopamine depletion in the striatum and motor symptoms like slow movement, muscle stiffness, and tremors.

Existing treatments for Parkinson's disease offer only symptomatic relief. Prolonged use of certain dopamine precursor drugs has diminishing returns and long-term complications such as involuntary movements. Inhibition of GPR6 presents a different therapeutic strategy, potentially addressing motor symptoms without triggering the current side effects.

In the study, "Structural insights into the high basal activity and inverse agonism of the orphan receptor GPR6 implicated in Parkinson's disease," published in Science Signaling, the research team focused on understanding the mechanisms behind GPR6's high activity.

Using advanced imaging techniques and an engineered version of human GPR6 suitable for crystallisation, researchers determined the receptor's structure in different states, including when it's inactive, partially active, and fully active. They also examined how it interacts with specific drugs that can reduce its activity.

The experiments revealed a lipid-like molecule occupying the orthosteric ligand-binding pocket. A cryo-EM structure of the fully active GPR6-G_s protein complex showed that the lipid-like molecule stabilises an active-like conformation of GPR6, suggesting that endogenous lipids may play a role in its activity.

These findings provide a fresh framework for understanding GPR6 function with a detailed basis for structure-based drug design, offering hope for improved future treatments of Parkinson's disease.