orphan G protein-coupled receptor 161, member of the class A family of seven-transmembrane G protein-coupled receptors
GPR161, an orphan GPCR, is a negative regulator of Sonic hedgehog (Shh) signaling, which promotes the processing of zinc finger protein GLI3 into its transcriptional repressor form (GLI3R) during neural tube development. In the absence of Shh, this proteolytic processing is normally mediated by cAMP-dependent protein kinase A (PKA). GPR161 is recruited to primary cilia by a mechanism depends on TULP3 (tubby-related protein 3) and the intraflagellar complex A (IFT-A). Moreover, Gpr161 knockout mice show phenotypes observed in Tulp3/IFT-A mutants, and cause increased Shh signaling in the neural tube. Taken together, GPR161 negatively regulates the PKA-dependent GLI3 processing in the absence of Shh signal by coupling to G(s) protein, which causes activation of adenylate cyclase, elevated cAMP levels, and activation of PKA. Conversely, in the presence of Shh, GPR161 is removed from the cilia by internalization into the endosomal recycling compartment, leading to downregulation of its activity and thereby allowing Shh signaling to proceed. In addition, GPR161 is over-expressed in triple-negative breast cancer (lacking estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 (HER2) expression) and correlates with poor prognosis. Mutations of GPR161 have also been implicated as a novel cause for pituitary stalk interruption syndrome (PSIS), a rare congenital disease of the pituitary gland. GPR161 is a member of the class A family of GPCRs, which contains receptors for hormones, neurotransmitters, sensory stimuli, and a variety of other ligands. All GPCRs have a common structural architecture comprising of seven-transmembrane (TM) alpha-helices interconnected by three extracellular and three intracellular loops. A general feature of GPCR signaling is agonist-induced conformational changes in the receptors, leading to activation of the heterotrimeric G proteins, which consist of the guanine nucleotide-binding G-alpha subunit and the dimeric G-beta-gamma subunits. The activated G proteins then bind to and activate numerous downstream effector proteins, which generate second messengers that mediate a broad range of cellular and physiological processes.
Comment:based on the structures of some class A family members with bound ligands (peptides or chemicals), agonists, or antagonists
Comment:Small-molecule chemical ligands tend to bind deeper within the receptor core, compared to a peptide ligand neurotensin, which binds towards the extracellular surface of its receptor.
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