GPR6 is an orphan G protein-coupled receptor that exhibits constitutive activity, maintaining high cAMP levels through G(s) protein activation 1. The receptor demonstrates dual G protein coupling, activating both stimulatory G(s) and inhibitory G(i/o) proteins, with pertussis toxin treatment enhancing its adenylyl cyclase stimulation 1. GPR6 can be activated by lipid-derived ligands including sphingosine 1-phosphate and dihydrosphingosine 1-phosphate at nanomolar concentrations 1. Recent structural studies revealed endogenous lipid-like ligands bound to the orthosteric pocket, contributing to its high constitutive activity 2. GPR6 is predominantly expressed in the brain, particularly in D2-type dopamine receptor-expressing medium spiny neurons of the striatopallidal pathway 2. The receptor is implicated in Parkinson's disease pathophysiology, as this pathway becomes aberrantly hyperactivated in the condition 2. Cannabidiol acts as an inverse agonist at GPR6, reducing β-arrestin2 recruitment in a concentration-dependent manner 3. The inverse agonist CVN424 showed therapeutic promise, improving motor symptoms in Parkinson's disease patients during clinical trials 2. GPR6 represents a potential therapeutic target for neurological disorders through modulation of its constitutive signaling activity.