Structural insights into the high basal activity and inverse agonism of the orphan receptor GPR6 implicated in Parkinson's disease.

Autor: Barekatain, Mahta, Johansson, Linda C., Lam, Jordy H., Chang, Hao, Sadybekov, Anastasiia V., Han, Gye Won, Russo, Joseph, Bliesath, Joshua, Brice, Nicola L., Carlton, Mark B. L., Saikatendu, Kumar S., Sun, Hukai, Murphy, Sean T., Monenschein, Holger, Schiffer, Hans H., Popov, Petr, Lutomski, Corinne A., Robinson, Carol V., Liu, Zhi-Jie, Hua, Tian
Zdroj: Science Signaling; 12/3/2024, Vol. 17 Issue 865, p1-18, 18p
Abstrakt: 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. 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. In addition, we obtained a cryo–electron microscopy structure of the signaling complex between GPR6 and its cognate Gs heterotrimer. The pseudo-apo structure revealed a strong density in the orthosteric pocket of GPR6 corresponding to a lipid-like endogenous ligand. A combination of site-directed mutagenesis, native mass spectrometry, and computer modeling suggested potential mechanisms for high constitutive activity and inverse agonism in GPR6 and identified a series of lipids and ions bound to the receptor. The structures and results obtained in this study could guide the rational design of drugs that modulate GPR6 signaling. Editor's summary: The rigidity and immobility caused by the progression of Parkinson's disease are caused by loss of dopaminergic neurons in the substantia nigra. Dopamine replacement therapy offers only temporary relief with potentially severe side effects. Barekatain et al. performed structural analysis of GPR6, a G protein–coupled receptor important for the activity of dopaminergic neurons that stop movement. An inverse agonist for GPR6 that is currently in clinical trials ameliorates locomotor deficits related to Parkinson's disease. The authors' data provide the structural basis for the high basal activity of GPR6 and how other inverse agonists targeting GPR6 could be designed to provide a nondopaminergic treatment option for patients with Parkinson's disease. —Wei Wong [ABSTRACT FROM AUTHOR]
Databáze: Complementary Index