Primary cilia, A-kinase anchoring proteins and constitutive activity at the orphan G protein-coupled receptor GPR161: A tale about a tail.

Primary cilia are non-motile antennae-like structures responsible for sensing environmental changes in most mammalian cells. Ciliary signalling is largely mediated by the Sonic Hedgehog (Shh) pathway, which acts as a master regulator of ciliary protein transit and is essential for normal embryonic development. One particularly important player in primary cilia is the orphan G protein-coupled receptor, GPR161. In this review, we introduce GPR161 in the context of Shh signalling and describe the unique features on its C-terminus such as PKA phosphorylation sites and an A-kinase anchoring protein motif, which may influence the function of the receptor, cAMP compartmentalisation and/or trafficking within primary cilia. We discuss the recent putative pairing of GPR161 and spexin-1, highlighting the additional steps needed before GPR161 could be considered 'deorphanised'. Finally, we speculate that the marked constitutive activity and unconventional regulation of GPR161 may indicate that the receptor may not require an endogenous ligand.