GPR161

G protein-coupled receptor that acts as a key inhibitor of the smoothened signaling pathway in primary cilia. Inhibits the smoothened signaling pathway in absence of hedgehog (DHH, IHH or SHH) by promoting formation of the transcription repressor form of GLI2 and GLI3 transcription factors. GPR161 activation triggers signaling via guanine nucleotide-binding protein G(s)/GNAS, mediating activation of adenylate cyclase activity and production of cAMP. Increased cAMP levels activate PKA, promoting PKA-dependent processing of GLI2 and GLI3 transcription factors, leading to formation of transcription repressor GLI2R and GLI3R, which repress expression of target genes. GPR161 also activates PKA by acting as a PKA-anchoring protein, which directly associates with type I PKA regulatory subunits (PRKAR1A and/or PRKAR1B), recruiting PKA followed by PKA-dependent processing of GLI2 and GLI3 transcription factors. In presence of hedgehog, GPR161 is removed from primary cilia by smoothened (SMO), preventing its activity and allowing activation of the smoothened signaling (By similarity). In contrast to the majority of G protein-coupled receptors, it is not activated by a ligand and it either acts as a constitutively active receptor or as a mechanosensitive receptor. Involved in regulation of the smoothened signaling pathway during early neural tube development, forelimb formation, skeletal development, embryonic cerebellar development and forebrain development (By similarity). Involved in the saltatory migration of neurons during brain development by acting as a mechanosensitive receptor that senses mechanical forces generated by fluid shear stress (By similarity)..

Function from UniProtKB (Q8N6U8), read 2026-09-23. CC BY 4.0.