Adhesion G Protein-Coupled Receptors: From In Vitro Pharmacology to In Vivo Mechanisms

Abstract

The adhesion family of G protein-coupled receptors (aGPCRs) comprises 33 members in humans. aGPCRs are characterized by their enormous size and complex modular structures. While the physiologic importance of many aGPCRs has been clearly demonstrated in recent years, the underlying molecular functions have only recently begun to be elucidated. In this minireview, we present an overview of our current knowledge on aGPCR activation and signal transduction with a focus on the latest findings regarding the interplay between ligand binding, mechanical force, and the tethered agonistic Stachel sequence, as well as implications on translational approaches that may derive from understanding aGPCR pharmacology.

Graphical abstract

Fig. 1.

Structural components of a generic aGPCR. aGPCRs undergo autoproteolytic cleavage in the endoplasmic reticulum at a highly conserved cleavage site that lies within the GPS motif, which is encompassed by the larger GAIN domain. This cleavage event divides the receptor into an N-terminal fragment and a C-terminal fragment. The NTF often contains conserved domains found in other proteins [(LRR, Ig, EGF) and, along with most of the GAIN domain, comprises the majority of the extracellular domain. The CTF consists of a residual part of the GAIN domain/ECD, the 7TM domain, and the intracellular domain (ICD). The activating Stachel sequence is located within the residual ECD. (Figure 1 was adapted to include the Stachel sequence from Liebscher et al., 2014a: New functions and signaling mechanisms for the class of adhesion G protein–coupled receptors, Ines Liebscher, Annals of the New York Academy of Sciences, 2014 Dec;1333:43–64; Copyright 2014, Copyright owner: Wiley-Blackwell.)

Fig. 2.

Proposed activation mechanisms of GPCRs. (A) Canonical modes of GPCR activation include the binding of an agonist with high affinity to its cognate-binding pocket for classic rhodopsin-like GPCRs. An exception lies with the protease-activated receptors that expose a cryptic tethered agonistic region upon cleavage by a protease, which then activates the receptor. Synthetic peptides that mimic the tethered peptide sequence can also activate PARs (Vu et al., 1991a,b). (B) Different activation mechanisms are proposed for aGPCRs. Similar to PARs, they possess a cryptic tethered agonist region, the Stachel sequence (S). Synthetic peptides derived from the Stachel amino acid sequence can activate aGPCRs. The activating Stachel sequence could be exposed upon NTF removal, which can then allow for CTF-mediated intracellular function(s) and independent NTF function(s). For GPR126 in peripheral nervous system development, Stachel exposure may require interaction with the ECM molecule Laminin-211, which directs subsequent mechanical activation as proposed by Petersen et al. (2015). Mechanical stimulation of aGPCR has also been suggested for Latrophilin/CIRL in sensory neurons (Scholz et al., 2015), while other studies have shown a direct activation of aGPCRs through interactions with collagens (Luo et al., 2014; Paavola et al., 2014).