Mechanisms of adhesion G protein–coupled receptor activation

Abstract

Adhesion G protein coupled receptors (AGPCRs) are a thirty-three-member subfamily of Class B GPCRs that control a wide array of physiological processes and are implicated in disease. AGPCRs uniquely contain large, self-proteolyzing extracellular regions that range from hundreds to thousands of residues in length. AGPCR autoproteolysis occurs within the extracellular GPCR Autoproteolysis-Inducing (GAIN) domain that is proximal to the N-terminus of the G protein-coupling seven transmembrane spanning (7TM) bundle. GAIN domain-mediated self-cleavage is constitutive and produces two-fragment holoreceptors that remain bound at the cell surface. It has been of recent interest to understand how AGPCRs are activated in relation to their two-fragment topologies. Dissociation of the AGPCR fragments stimulates G protein signaling through the action of the tethered-peptide-agonist stalk that is occluded within the GAIN domain in the holoreceptor form. AGPCRs can also signal independently of fragment dissociation, and a few receptors possess GAIN domains incapable of self-proteolysis. This has resulted in complex theories as to how these receptors are activated in vivo, complicating pharmacological advances. Currently there is no existing structure of an activated AGPCR to support any of the theories. Further confounding AGPCR research is that many of the receptors remain orphans and lack identified activating ligands. In this review, we provide a detailed layout of the current theorized modes of AGPCR activation with discussion of potential parallels to mechanisms used by other GPCR classes. We provide a classification means for the ligands that have been identified and discuss how these ligands may activate AGPCRs in physiological-contexts.

G protein-coupled receptors: structure- and function-based drug discovery

“…Adhesion receptors can also signal independently of fragment dissociation and this has complicated pharmacological consequences. 22 , 24 , 25 …”

“…Two ADGRG1/ADGRG5 modulators, dihydromunduletone and 3-α-acetoxydihydrodeoxygedunin developed via drug screening efforts, showed disease-related efficacy changes thereby calling for exploration of their activities in a pathological environment. 24 , 25 However, associated drug resistance may not only hamper disease but also offer insights into potential mechanisms of such resistance and strategies to tackle it.…”

“…Adhesion receptors can also signal independently of fragment dissociation and this has complicated pharmacological consequences. 22,24,25 In this class, receptors of glucagon family peptides, followed by CGRP, PTH, GHRH, CRF, VIP, and PACAP, constitute major targets for therapeutic intervention (Table S1) of various diseases, including obesity, T2DM, osteoporosis, migraine, depression, and anxiety. 26,27 To date, multiple GLP-1 receptor (GLP-1R) agonists have been developed by a combination of selective amino acid substitutions, enzymatic cleavage blockade, and conjugation to entities that increase binding to plasma proteins.…”

Latrophilin GPCR signaling mediates synapse formation

“…Adhesion-GPCRs characteristically contain large extracellular sequences with multiple potential ligand-binding domains and a canonical GAIN domain that is coupled to the seven-transmembrane region module characteristic of GPCRs (reviewed in Vizurraga et al, 2020 ; Morgan et al, 2019 ; Folts et al, 2019 ; Purcell and Hall, 2018 ). Most adhesion-GPCRs additionally have a long cytoplasmic region.…”

“…The central role of latrophilins as postsynaptic adhesion-GPCRs in synapse formation raises the question whether latrophilins actually function as GPCRs in synapse formation. An intrinsic GPCR signaling activity was suggested for several adhesion-GPCRs, including latrophilins ( Purcell and Hall, 2018 ; Nazarko et al, 2018 ; Müller et al, 2015 ; Ovando-Zambrano et al, 2019 ; Scholz et al, 2017 ; Araç et al, 2016 ; Kishore et al, 2016 ; Liebscher et al, 2014 ; Vizurraga et al, 2020 ). However, few data exist for the physiological role of mammalian adhesion-GPCRs in general, and for their GPCR activity in particular.…”