G protein-coupled receptor 161 (GPR161)

G protein-coupled receptor 161 (GPR161) is an orphan G protein-coupled receptor broadly classified within the Class A (Rhodopsin-like) receptor family[1][4]. It is primarily localized to primary cilia, where it functions as a key negative regulator of Hedgehog (Hh) signaling, chiefly by promoting cAMP-dependent protein kinase A (PKA) activation. Elevated cAMP via GPR161 suppresses Hh pathway activation by stimulating the conversion of GLI transcription factors into their repressor forms, critical for proper neural tube and organ development[1][3][4]. Constitutively active due to unique self-activation via its extracellular loop and possibly sterol interaction, GPR161 is essential for neural fold apposition and lens, CNS, and limb development. Overexpression has been linked to cancer, especially in subtypes such as triple-negative breast cancer[4]. No endogenous ligand has been confirmed, but the receptor presents a potential druggable site in its extrahelical sterol-binding pocket[1]. Inhibition or loss of GPR161 function leads to inappropriate Hh pathway activation, with implications for developmental disorders and malignancy[1][2][4].

Other names

GPR161RE2G-protein coupled receptor RE2G-protein coupled receptor 161

Modulation of cAMP signaling via G_s protein coupling; Regulation of protein kinase A (PKA) activity in primary cilia; Negative regulation of Hedgehog signaling through GLI repression