GPR161 is an orphan G protein-coupled receptor that serves as a critical negative regulator of Hedgehog signaling during neural development 1. Located at the primary cilium, GPR161 increases cAMP levels to activate PKA-dependent phosphorylation of GLI3, promoting its conversion to the repressor form GLI3R and suppressing Hedgehog pathway activity 1. GPR161 is recruited to cilia through interactions with the IFT-A complex and functions as part of a macromolecular signaling complex with PKA holoenzymes 1. Upon Hedgehog activation, GPR161 undergoes phosphorylation by GRK2, recruits β-arrestins, and is exported from cilia via the BBSome and IFT machinery, allowing Hedgehog signaling activation 2. Structurally, GPR161 contains an unusual extracellular loop occupying the ligand pocket and binds sterols that stabilize Gs coupling, though its cognate ligand remains unknown 3. Recent evidence reveals GPR161 functions as a mechanoreceptor at primary cilia, with its helix 8 sensing fluid shear stress to regulate neuronal migration through cAMP/PKA-mediated phosphorylation of NDE1 4. GPR161 dysfunction is associated with medulloblastoma development 5, and targeting GPR161-mediated Hedgehog signaling shows therapeutic potential in inflammatory disease models 5.