Adhesion GPCRs as a paradigm for understanding polycystin-1 G protein regulation

Polycystin-1, whose mutation is the most frequent cause of autosomal dominant polycystic kidney disease, is an extremely large and multi-faceted membrane protein whose primary or proximal cyst-preventing function remains undetermined. Accumulating evidence supports the idea that modulation of cellular signaling by heterotrimeric G proteins is a critical function of polycystin-1. The presence of a cis-autocatalyzed, G protein-coupled receptor (GPCR) proteolytic cleavage site, or GPS, in its extracellular N-terminal domain immediately preceding the first transmembrane domain is one of the notable conserved features of the polycystin-1-like protein family, and also of the family of cell adhesion GPCRs. Adhesion GPCRs are one of five families within the GPCR superfamily and are distinguished by a large N-terminal extracellular region consisting of multiple adhesion modules with a GPS-containing GAIN domain and bimodal functions in cell adhesion and signal transduction. Recent advances from studies of adhesion GPCRs provide a new paradigm for unraveling the mechanisms by which polycystin-1-associated G protein signaling contributes to the pathogenesis of polycystic kidney disease. This review highlights the structural and functional features shared by polycystin-1 and the adhesion GPCRs and discusses the implications of such similarities for our further understanding of the functions of this complicated protein.