Pathophysiological impact of the adhesion G protein-coupled receptor family

Abstract

G protein-coupled receptors (GPCRs) represent one of the most targeted drug classes in the human genome, accounting for greater than 40% of all Food and Drug Administration-approved drugs. However, the second-largest family of GPCRs, known as adhesion GPCRs (aGPCR), have yet to serve as a clinical target despite increasing evidence of their physiological and pathological functions, which suggests an opportunity toward the development of novel therapeutics. To date, the pathophysiological function of aGPCRs is associated with a plethora of diseases including cancer, central nervous system disorders, immunity and inflammation, and others. To highlight their potential as pharmacological targets, we will review three distinct aGPCR members (ADGRG1, ADGRE5, and ADGRF5), highlighting their molecular mechanisms of action and contributions to the development of pathophysiology.

Keywords: GPCR; pathophysiology; signaling.

Graphical abstract

Figure 1.

General structural representation of adhesion GPCRs (aGPCRs). aGPCRs are structurally unique G protein-coupled receptors (GPCRs) that possess long extracellular regions. These receptors undergo an autocatalytic event within their canonical GAIN domain at the conserved GPS site due to nucleophilic attack of its tethered Stachel sequence that results in two cleaved portions, specifically, an “adhesive” N-terminal fragment and a truncated “signaling” C-terminal fragment. aGPCRs possess various modes of receptor activation such as peptide or small ligand agonist binding, mechanical force, or autoproteolytic induction. [Figure was partly designed using Servier Medical Art, provided by Servier, licensed under a Creative Commons Attribution 3.0 unported license.]