Protein smoothened

G protein-coupled receptor, which transduces the smoothened signaling pathway (PubMed:19592253, PubMed:27437577, PubMed:28344083, PubMed:31168089, PubMed:32929279, PubMed:36202993). Activated by cholesterol in response to hedgehog (DHH, IHH or SHH) morphogens (PubMed:27437577, PubMed:28344083, PubMed:32929279). In absence of hedgehog, SMO is inactivated by patched protein (PTCH1 or PTCH2), which prevents SMO access to cholesterol (PubMed:28344083). In response to hedgehog-binding to pathched, inhibition is relieved, promoting SMO translocation to primary cilium and activation by cholesterol: cholesterol causes a conformation change that triggers signaling via G protein G(i), mediating inhibition of adenylate cyclase activity and decreassed production of cAMP (PubMed:28344083, PubMed:31168089). Decreased cAMP levels then inhibit protein kinase A (PKA) and promote release of GLI (GLI1, GLI2 and GLI3) transcription factors, which activate expression of target genes (PubMed:31168089). Active SMO also directly inhibits PKA by sequestering its catalytic subunit, PRKACA, at the cell membrane, preventing PRKACA-mediated phosphorylation and subsequent processing of GLI transcription factors (PubMed:36202993, PubMed:39138140). Active SMO also promotes the removal of GPR161, a key inhibitor of the smoothened signaling pathway, from primary cilia (By similarity)