Adhesion G Protein–Coupled Receptors as Drug Targets

Abstract

The adhesion G protein-coupled receptors (aGPCRs) are an evolutionarily ancient family of receptors that play key roles in many different physiological processes. These receptors are notable for their exceptionally long ectodomains, which span several hundred to several thousand amino acids and contain various adhesion-related domains, as well as a GPCR autoproteolysis-inducing (GAIN) domain. The GAIN domain is conserved throughout almost the entire family and undergoes autoproteolysis to cleave the receptors into two noncovalently-associated protomers. Recent studies have revealed that the signaling activity of aGPCRs is largely determined by changes in the interactions among these protomers. We review recent advances in understanding aGPCR activation mechanisms and discuss the physiological roles and pharmacological properties of aGPCRs, with an eye toward the potential utility of these receptors as drug targets.

Adhesion G protein–coupled receptors—Candidate metabotropic mechanosensors and novel drug targets

“…However, observations of Stachel ‐independent signalling require the consideration of different and more complex activation scenarios for aGPCR . This is supported by the discovery of non‐canonical signal conduits directly engaging with individual aGPCR homologues.…”

“…One obvious setting that may account for the liberation of the Stachel is the physical removal of the NTF through mechanical force since the lack of known covalent bonds between NTF and CTF. Interactions between the eponymous adhesion domains contained within the NTF of most aGPCR and matricellular or other membrane‐exposed proteins are well documented and mark yet another exception of aGPCR from the rule (Table ), as GPCR usually engage soluble ligands such as biogenic amines, peptides or hormones, to name a few ligand classes . Forces transmitted through the interaction of aGPCR ECR and fixed ligand partners (Table ) may prove strong enough to dislodge the Stachel from its GAIN domain encasing, although such forces have not been experimentally determined yet.…”

The ion channel function of polycystin‐1 in the polycystin‐1/polycystin‐2 complex

“…In contrast, despite intensive studies for over 20 years, the roles of PC1 are largely unknown. Indeed, PC1 has significant similarities to the adhesion G proteincoupled receptors (aGPCRs), a large group of proteins involved in many signaling pathways [28]. The N-terminus of PC1 contains well-recognized motifs involved in protein-protein, protein-saccharide, and protein-ligand interactions.…”

“…Thus, PC1 is generally thought to function as a cell surface receptor [2,3,26,27]. Indeed, PC1 has significant similarities to the adhesion G proteincoupled receptors (aGPCRs), a large group of proteins involved in many signaling pathways [28]. Like aGPCRs, PC1 contains a GPCR autoproteolysis-inducing (GAIN) domain located upstream of the first transmembrane domain and undergoes autoproteolytic cleavage at a G protein-coupled receptor proteolysis site (GPS) within the GAIN domain [29,30].…”

Synaptamide activates the adhesion GPCR GPR110 (ADGRF1) through GAIN domain binding

“…aGPCRs have been shown to regulate diverse physiological processes and to be associated with various human disease conditions such as bilateral frontoparietal polymicrogyria and usher syndrome, thus presenting a potential for drug discovery [5][6][7][8][9][10][11] . At present, no aGPCR-targeting drugs have been reported, in part because most aGPCRs remain orphan and the molecular mechanism of aGPCRs activation is poorly understood 12 . aGPCR signaling has been proposed to involve GAIN-mediated autoproteolysis and Stachel agonism 3,4 .…”