Orphan G protein-coupled receptors (GPCRs): biological functions and potential drug targets

Abstract

The superfamily of G protein-coupled receptors (GPCRs) includes at least 800 seven-transmembrane receptors that participate in diverse physiological and pathological functions. GPCRs are the most successful targets of modern medicine, and approximately 36% of marketed pharmaceuticals target human GPCRs. However, the endogenous ligands of more than 140 GPCRs remain unidentified, leaving the natural functions of those GPCRs in doubt. These are the so-called orphan GPCRs, a great source of drug targets. This review focuses on the signaling transduction pathways of the Adhesion GPCR family, the LGR subfamily, and the PSGR subfamily, and their potential functions in immunology, development, and cancers. In this review, we present the current approaches and difficulties of orphan GPCR deorphanization and characterization.

Intrinsic disorder in spondins and some of their interacting partners

“…Regions 95-100 and 147-152 of Fzd8 are involved in Wnt binding, motif Lys-Thr-X-X-X-Trp located at 608-613 region mediates interaction with the PDZ domain of Dvl family members, and a PDZ-binding motif is located the very end of C-terminus (residues 692-694). Figure 9B shows that Fzd8 is predicted to have several IDPRs (residues 1-33, 156-249, 340-380, 516-526, 574-580, and 625-694) 4 disorder-based potential binding sites (residues [148][149][150][151][152][153][154][155][156][157][158][159][160][196][197][198][199][200][201][202][203][204][205][206][207][208][209][210], 666-679, and 687-694), and several phosphorylation sites. Two functional motifs/regions of Fzd8 (one of the Dvl binding motifs (residues 147-152) and C-terminal PDZ-binding motif) are located within the disordered regions that are expected to undergo binding-induced disorder-to-order transitions, clearly indicating that intrinsic disorder is important for the functionality of this transmembrane protein (see Fig.…”

“…157 Various physiological and pathological roles of GPCRs rely on the ability of these receptors to transduce extracellular signals to various intracellular pathways via their activation mediated by binding to a broad range of ligands, such as eicosanoids, organic compounds, peptides, and proteins. 157 Until quite recently, LGRs were considered as orphan GPCRs, since their endogenous ligands remained unidentified. However, it is known now that LGRs belong to the Rhodopsin subfamily of GPCRs, being typically considered as classical GPCRs in terms of their structure and signal transduction.…”

“…However, it is known now that LGRs belong to the Rhodopsin subfamily of GPCRs, being typically considered as classical GPCRs in terms of their structure and signal transduction. 157 Based on their natural ligands, LGRs 4-8 can be grouped into 2 classes, with R-spondins being the ligands for the LGRs 4, 5, and 6, 52 and with the relaxin family peptide (RXFP) serving as a ligand for the LGRs 7 and 8. 158 The LGR 4-6 proteins are known to interact with Wnt receptors, mediate R-spondin signaling, and lead directly to the activation of Wnt canonical pathway through the Frizzled and LRP proteins.…”

Characterization of G Protein-coupled Receptors by a Fluorescence-based Calcium Mobilization Assay

“…The deorphanization of these receptors will improve the understanding of their physiological roles in organisms and may uncover putative targets for new drug applications 7 .…”

A new era for GPCR research: structures, biology and drug discovery

“…Lappano and Maggiolini provide a systematic review on the relationship of cancers with various subfamilies of GPCRs, which may serve as the basis for developing novel pharmacological interventions for cancers [7] . A large number of GPCRs are orphan [8] . Finally, as one of the most important drug targets, GPCRs are widely pursued by both academic and industrial research for drug discovery.…”