International Union of Basic and Clinical Pharmacology. XCIV. Adhesion G protein-coupled receptors

Abstract

The Adhesion family forms a large branch of the pharmacologically important superfamily of G protein-coupled receptors (GPCRs). As Adhesion GPCRs increasingly receive attention from a wide spectrum of biomedical fields, the Adhesion GPCR Consortium, together with the International Union of Basic and Clinical Pharmacology Committee on Receptor Nomenclature and Drug Classification, proposes a unified nomenclature for Adhesion GPCRs. The new names have ADGR as common dominator followed by a letter and a number to denote each subfamily and subtype, respectively. The new names, with old and alternative names within parentheses, are: ADGRA1 (GPR123), ADGRA2 (GPR124), ADGRA3 (GPR125), ADGRB1 (BAI1), ADGRB2 (BAI2), ADGRB3 (BAI3), ADGRC1 (CELSR1), ADGRC2 (CELSR2), ADGRC3 (CELSR3), ADGRD1 (GPR133), ADGRD2 (GPR144), ADGRE1 (EMR1, F4/80), ADGRE2 (EMR2), ADGRE3 (EMR3), ADGRE4 (EMR4), ADGRE5 (CD97), ADGRF1 (GPR110), ADGRF2 (GPR111), ADGRF3 (GPR113), ADGRF4 (GPR115), ADGRF5 (GPR116, Ig-Hepta), ADGRG1 (GPR56), ADGRG2 (GPR64, HE6), ADGRG3 (GPR97), ADGRG4 (GPR112), ADGRG5 (GPR114), ADGRG6 (GPR126), ADGRG7 (GPR128), ADGRL1 (latrophilin-1, CIRL-1, CL1), ADGRL2 (latrophilin-2, CIRL-2, CL2), ADGRL3 (latrophilin-3, CIRL-3, CL3), ADGRL4 (ELTD1, ETL), and ADGRV1 (VLGR1, GPR98). This review covers all major biologic aspects of Adhesion GPCRs, including evolutionary origins, interaction partners, signaling, expression, physiologic functions, and therapeutic potential.

Fig. 1.

Representation of the phylogenetic relationships of Adhesion GPCRs and their N-terminal domain architecture. Adhesion GPCRs can be subdivided into nine distinct subfamilies with 33 homologs in the human genome on the basis of phylogenetic analysis of the conserved 7TM domain region. Each subfamily has a unique combination of N-terminal domains and varies widely in length of their N termini. The conserved sequence motif within the GPS, found within the GAIN domain of most Adhesion GPCRs, mediates autoproteolysis and subsequent attachment of the cleaved NTF and CTF fragments. All subfamilies share a GAIN and 7TM domain (Adhesion GPCR signature), whereas the depicted N-terminal functional domains are not present in every homolog of the subfamilies. ADGRA1 (GPR123) is exceptional as it is the only mammalian adhesion GPCR that does not contain a GAIN domain. Of note, improper GPS motifs that (may) preclude cleavage are found in more Adhesion GPCRs. Open GPS symbols indicate Adhesion GPCRs that do not undergo cleavage, according to experimental evidence. The tree topology shown on the left was obtained from consensus of previous phylogenetic studies of Adhesion GPCRs (Bjarnadóttir et al., 2004; Gloriam et al., 2007; Haitina et al., 2009). It should be noted that the hierarchy within some of these divergent subfamilies, such as VI (ADGRFs) and VIII (ADGRGs), may vary in a few nodes, depending on the methodology, dataset, and parameters used in each phylogenetic analysis. Calx, calnexin; CUB, Cs1 and Csr/Uegf/BMP1; EGF_CA, calcium-binding EGF; EPTP, epitempin; HRM, hormone receptor motif; I-set, immunoglobulin I-set domain; LRR, leucine-rich repeat; PTX, pentraxin; RBL, rhamnose-binding lectin; SEA, sperm protein, enterokinase, agrin module; TSP, thrombospondin.

Fig. 2.

Cleavage- and topology-based compartmentation of Adhesion GPCR architecture. Most Adhesion GPCRs undergo autoproteolysis at the GPS within their GAIN domain, resulting in a two-partite structure containing the NTF and the CTF (left). Alternatively, the protein layout of all Adhesion GPCRs is marked by a three-partite structure consisting of an ECD, a 7TM domain, and an ICD.

Fig. 3.

The GAIN domain and GPS autoproteolysis. Diagram of an Adhesion-GPCR. The GAIN domain, located at the C-terminal half of the NTF, consists of A-subdomain (green) and B-subdomain (light blue). The GPS motif, which is a part of subdomain B, is colored yellow. The proposed mechanism of the GPS autoproteolytic reaction is shown inside the black circle. A histidine or another general base withdraws a proton from the hydroxyl group of a serine or threonine at position +1. The resulting negatively charged oxygen makes a nucleophilic attack on the carbonyl group of the residue at position –1 (e.g., a leucine), yielding a tetrahedral intermediate and subsequently an ester intermediate. The resulting ester is then hydrolyzed to produce the NTF and CTF that form the final mature protein.

Fig. 4.

Representation of Adhesion GPCR interactions within the NTFs. As examples, interactions of the Adhesion GPCRs (A) ADGR5 (CD97), (B) ADGRG1 (GPR56), (C) ADGRG6 (GPR126), (D and E) ADGRL1 (latrophilin-1), and (F) ADGRB3 (BAI3) are depicted. The interactions of the binding partners with the receptors are shown in cis and trans configurations. Arrows indicate the protein domains—as far as these are known—that facilitate the interactions. The figure also shows some of the solved three-dimensional structures of protein domains, including RBL domain (PDB ID 2JX9) and tissue transglutaminase 2 (PDB ID 1KV3) obtained from the PDB database. The three-dimensional structure of chondroitin sulfate B (a glycosaminoglycan) has been obtained from the PubChem Compound Database (compound ID: 32756). CUB, Cs1 and Csr/Uegf/BMP1; EGF_CA, calcium-binding EGF; FG–GAP, phenylalanine-glycine–glycine-alanine-proline; GPI, glycosylphosphatidylinositol; HRM, hormone receptor motif; LRR, leucine-rich repeat; LRRCT, leucine-rich repeat C-terminal; LRRNT, leucine-rich repeat N-terminal; NHL, NCL-1, HT2A, and Lin-41; PH, Pleckstrin homology; RBL, rhamnose-binding lectin; RGD, arginine-glycine-aspartate; START, StAR-related lipid-transfer; YD, tyrosine-aspartate.

Fig. 5.

Expression of Adhesion GPCRs. Summary of available published data on the expression of Adhesion GPCRs in (A) humans and (B) mice and rats, obtained by transcriptional profiling and protein analysis techniques. For additional information and references, see the descriptions of individual Adhesion GPCRs at http://www.guidetopharmacology.org/.

Fig. 5.

Expression of Adhesion GPCRs. Summary of available published data on the expression of Adhesion GPCRs in (A) humans and (B) mice and rats, obtained by transcriptional profiling and protein analysis techniques. For additional information and references, see the descriptions of individual Adhesion GPCRs at http://www.guidetopharmacology.org/.

Fig. 6.

Functional involvement of Adhesion GPCRs. Summary of available published data on the function of Adhesion GPCRs, obtained in vitro and in vivo from humans and mouse models.