Versatile Signaling Activity of Adhesion GPCRs

The adhesion G protein-coupled receptors (aGPCRs) are a family of 33 receptors in humans that are widely expressed in various tissues and involved in many diverse biological processes. These receptors possess extremely large N-termini (NT) containing a variety of adhesion domains. A distinguishing feature of these receptors is the presence within the NT of a highly conserved GPCR autoproteolysis-inducing (GAIN) domain, which mediates autoproteolysis of the receptors into N-terminal and C-terminal fragments that stay non-covalently associated. The downstream signaling pathways and G protein-coupling preferences of many aGPCRs have recently been elucidated, and putative endogenous ligands for some aGPCRs have also been discovered and characterized in recent years. A pivotal observation for aGPCRs has been that deletion or removal of the NT up the point of GAIN cleavage results in constitutive receptor activation. For at least some aGPCRs, this activation is dependent on the unmasking of specific agonistic peptide sequences within the N-terminal stalk region (i.e., the region between the site of GAIN domain cleavage and the first transmembrane domain). However, the specific peptide sequences involved and the overall importance of the stalk region for activation can vary greatly from receptor to receptor. An emerging theme of work in this area is that aGPCRs are capable of versatile signaling activity that may be fine-tuned to suit the specific physiological roles played by the various members of this family.