G protein-coupled receptor 3 (GPR3)

G protein-coupled receptor 3 (GPR3) is an orphan class A GPCR broadly expressed in the brain (hypothalamus, hippocampus, cortex) and peripheral tissues (liver, ovary)[1][5]. It is notable for its high constitutive activity, meaning it activates Gs proteins and elevates cAMP in the absence of a classical ligand. This intrinsic activity regulates diverse physiological functions, including neuronal growth, oocyte maturation, and adipose tissue thermogenesis[1][6][2]. GPR3 is implicated in Alzheimer’s disease, as it regulates γ-secretase activity and amyloid precursor protein processing, and is also involved in oocyte meiosis arrest and cold-induced adipose lipolysis[1][3][6]. Structural studies reveal a lipid-like molecule, possibly an endogenous lipid or fatty acid, binds within its hydrophobic orthosteric pocket, suggesting activation via a ubiquitous lipid ligand, although the precise endogenous ligand is still debated[1][5]. GPR3 operates via a constitutive coupling to Gs, driving cAMP signaling, and exhibits structural features typical of lipid-responsive GPCRs, including a dynamic hydrophobic tunnel[1][5]. No approved drugs target GPR3 clinically; however, inverse agonists and other tool compounds are under investigation as potential modulators for diseases such as Alzheimer’s disease[1][5].

Other names

ACCAGPR3ACCA orphan receptoradenylate cyclase constitutive activator

Constitutive activation of Gs protein, leading to increased adenylate cyclase activity and cAMP production[1][3][5] Inverse agonists reduce basal activity by stabilizing the inactive receptor conformation[1]