Characterization and functional study of a cluster of four highly conserved orphan adhesion‐GPCR in mouse

Abstract

Background: Adhesion G protein-coupled receptors (aGPCR) constitute a structurally and functionally diverse class of seven-transmembrane receptor proteins. Although for some of the members important roles in immunology, neurology, as well as developmental biology have been suggested, most receptors have been poorly characterized. Results: We have studied evolution, expression, and function of an entire receptor group containing four uncharacterized aGPCR: Gpr110, Gpr111, Gpr115, and Gpr116. We show that the genomic loci of these four receptors are clustered tightly together in mouse and human genomes and that this cluster likely derives from a single common ancestor gene. Using transcriptional profiling on wild-type and knockout/LacZ reporter knockin mice strains, we have obtained detailed expression maps that show ubiquitous expression of Gpr116, co-expression of Gpr111 and Gpr115 in developing skin, and expression of Gpr110 in adult kidney. Loss of Gpr110, Gpr111, or Gpr115 function did not result in detectable defects, indicating that genes of this aGPCR group might function redundantly. Conclusions: The aGPCR cluster Gpr110, Gpr111, Gpr115, and Gpr116 developed from one common ancestor in vertebrates. Expression suggests a role in epithelia, and one can speculate about a possible redundant function of GPR111 and GPR115. Developmental Dynamics 241:1591-1602, 2012.V C 2012 Wiley Periodicals, Inc.

Adhesion G protein-coupled receptors are activated by exposure of a cryptic tethered agonist

“…aGPCR GAIN domains are comprised predominantly of tightly packed β-strands and are sufficient to mediate autoproteolysis at the consensus site, HL/T ( Fig. 1) (8,14). β-strand-13 is buried deeply within the GAIN hydrophobic core and is an essential contributor to overall domain structural integrity despite being present C-terminal to the GAIN domain self-cleavage site.…”

“…1, Tunable Model). This model could account for how cleavage-deficient aGPCRs, such as GPR111 and GPR115, may activate G proteins (22). aGPCRs represent unexploited potential therapeutic targets (4-7).…”

Stachel-independent modulation of GPR56/ADGRG1 signaling by synthetic ligands directed to its extracellular region

“…For example, overexpression of autoproteolysis-deficient lat-1/ADGRL1 in lat-1-KO Caenorhabditis elegans rescues the WT phenotype, suggesting that some aGPCR functions do not require autoproteolysis (41). Additionally, there are several aGPCRs that lack the conserved residues critical for autoproteolysis and therefore, remain uncleaved (20,34). Furthermore, several aGPCRs, including GPR56, are found partially uncleaved in vivo (20,36,42).…”

“…Although it has been proposed that natural ligands may induce shedding on binding to N-terminal adhesion domains and thereby, activate the receptor, direct proof of ligand-induced shedding remains elusive. Several recent observations, including that some aGPCRs do not undergo autoproteolysis and therefore, cannot undergo shedding (20,34), have necessitated the introduction of a model, in which the ECR (i.e., associated NTF and Stachel) has a direct role in modulating the 7TM signaling (22,33,35,36). Regulation by this mechanism, which we term "Stachel-independent," is independent of Stachel-mediated activation, although the Stachel residues are present within the core of the GAIN domain (Fig.…”

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

“…The existence of cleavage-deficient aGPCR homologs owing to the lack of the consensus GPS site, like GPR123 (ADGRA1) or the conserved cleavage motif as in GPR111 (ADGRF2) and GPR115 (ADGRF4) (Prömel et al, 2012b), suggests that not all aGPCRs rely on a releasable NTF. Further, studies on LAT-1 in C. elegans have directly studied this phenomenon in vivo using the transgenic complementation assay described above.…”