GPR6, a G protein-coupled receptor, is primarily expressed in the medium spiny neurons of the striatum, specifically within the striatopallidal pathway. This pathway is heavily impacted by the loss of dopamine-producing neurons in Parkinson’s disease (PD). Targeting GPR6 presents a promising therapeutic approach for a nondopaminergic treatment of PD, which would offer reduced risk for dyskinesia and other side effects. Now, a new preclinical study sheds light on the structure and function of GPR6. The insights could guide future research and the rational design of more selective GPR6-targeting drugs that are more effective and have fewer side effects for patients.
The findings are published in Science Signaling in an article titled, “Structural Insights into the High Basal Activity and Inverse Agonism of the Orphan Receptor GPR6 Implicated in Parkinson’s Disease.”
“GPR6 is an orphan G protein-coupled receptor with high constitutive activity found in D2-type dopamine receptor–expressing medium spiny neurons of the striatopallidal pathway, which is aberrantly hyperactivated in Parkinson’s disease,” the researchers wrote. “Here, we solved crystal structures of GPR6 without the addition of a ligand (a pseudo-apo state) and in complex with two inverse agonists, including CVN424, which improved motor symptoms in patients with Parkinson’s disease in clinical trials.”
Parkinson’s disease causes tremors, rigidity, and a loss of mobility over time, eventually leaving patients disabled. This immobility occurs due to the death of dopamine-releasing (or dopaminergic) neurons in the substantia nigra, a small but vital area of the brain that controls movement and cognition.
Treatments for Parkinson’s disease that restore dopamine levels can temporarily relieve symptoms, but there is currently no therapy that can halt the underlying degeneration of these neurons. However, there are some promising treatments in early trials that target GPR6, which is abundant in some dopaminergic neurons. This receptor has high basal activity—meaning it can exert biological effects even when not bound to an activating ligand. Moreover, it is found in the dopaminergic neurons that stop movement, which tend to be unusually active in Parkinson’s disease.
Mahta Barekatain, PhD, from the University of Southern California, and collaborators used mass spectrometry, mutagenesis, and computer models to analyze the structure of G protein-bound GPR6. The researchers discovered potential mechanisms behind the high basal activity and inverse agonism of GPR6.
They also solved the structures of G protein-bound GPR6 in complex with two compounds that suppress its basal activity (or inverse agonists), including one named CVN424. CVN424 is a non-dopamine therapy that inhibits GPR6, and has shown promise in clinical trials.
The structures and results from the new study could guide the rational design of drugs that modulate GPR6 signaling.
