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.

Figure 1

Percentage of the orphan GPCRs in GPCR superfamily. GPCRs constitute a large transmembrane family of more than 800 members. Among them, 6% are utilized as drug target in clinical applications, and 30% are natural ligand receptors. However, 49% are olfactory receptors (most of them are orphan GPCRs), and 15% are orphan GPCRs. (Data were summarized from a review paper)

Figure 2

LGR subfamily GPCRs. The Type A LGRs includes the follicle-stimulating hormone receptor (FSHR), the luteinizing hormone receptor (LHR) and the thyroid-stimulating hormone receptor (TSHR). The Type B LGR comprises three members, Gpr48/LGR4, LGR5, and LGR6 which remain orphan GPCRs at the present time. By contrast, Type C LGRs have only two members, LGR7 and LGR8 which have been demonstrated to be the relaxin family receptors. Type A contains 9 LRRs in the ectodomain, whereas Type B contains 17 LRRs. By contrast, Type C has an N-terminal LDL receptor-like cysteine-rich domain not found in other LGRs. 7TM, seven-transmembrane; LDL, low-density lipoprotein; LRR, leucine-rich repeat; LGR, leucine-rich repeat-containing G-protein-coupled receptor; FSHR, follicle-stimulating hormone receptor; LHR, luteinizing hormone receptor; TSHR, thyroid-stimulating hormone receptor.

Figure 3

Schematic diagram of the extracellular N-terminal domain within the Adhesion GPCRs. The extracellular N-terminal domains of 33 Adhesion GPCRs was predicted by the RPS-BLAST against the conserved domain database (CCD). CA, cadherin domain; calx-beta, domain found in Na⁺–Ca²⁺ exchangers; CUB, resembles the structure of immunoglobins; EAR, epilepsy-associated repeat; EGF-Lam, laminin EGF-like domain; EGF, epidermal growth factor domain; HBD, hormone-binding domain; herpes-gp2, resembles the equine herpes virus glycoprotein gp2 structure; GBL, galactose-binding lectin domain; Ig, immunoglobulin domain; OLF, olfactomedin domain; LamG, laminin G domain; LRR, leucine-rich repeat domain; PTX, pentraxin domain; Puf, displays structural similarity to RNA-binding protein from the Puf family; SEA, domain found in sea-urchin sperm protein; SIN, resembles the primary structure of the SIN component of the histone deacetylase complex; TSP1, thrombospondin domain. C-type lectin, similar to the C-type lectin or carbohydrate-recognition domain; GPS, GPCR proteolytic site domain.