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GPCR Family

G protein-coupled receptors (GPCRs) are crucial eukaryotic signal transduction gatekeepers and represent the largest protein family in the human proteome, with exceed 800 members. They have a common architecture of seven transmembrane helices, and can be classified into five major classes and further divided into subfamilies based on sequence similarities (Figure 1). Located in the plasma membrane, GPCRs recognize a number of extracellular stimuli, including ions, small molecules, peptides and proteins, and transmit the resulting extracellular signals across the membrane over a distance of ~30 Å to elicit intracellular responses. Signal transmission occurs through coupling to different intracellular proteins (such as heterotrimeric G proteins, kinases and arrestins), which then activate downstream effectors and trigger cascades of cellular and physiological responses. GPCR-mediated signaling pathways have been related to many human diseases, and GPCRs are the targets of an estimated 30–40% of all drugs currently on the market.

Phylogenetic tree representation of the human GPCR superfamily.Figure 1. Phylogenetic tree representation of the human GPCR superfamily.

According to the basis of phylogenetic criteria, human GPCRs can be divided into five main families, including Glutamate, Rhodopsin, Adhesion, Frizzled/Taste2, and Secretin. Among the five GPCRs families, Rhodopsin is the most widely studied. The second largest GPCR family is the Adhesion family with 33 members. This family is very special due to its members’ secondary structures, with distinctive long N-termini containing adhesion domains. These studies have shown that Adhesion GPCRs are involved in the signaling of cell adhesion, motility, immune system and the embryonic development. There are still GPCRs for which the natural ligands need to be identified. These are called orphan GPCRs.

Rhodopsin GPCR family

Recently, the leucine-rich repeat containing G-protein coupled receptor (LGR) subfamily, part of Rhodopsin, have displayed enormously vital physiological functions in knockout mice studies especially LGR4 and LGR5. Olfactory receptors also belong to Rhodopsin family of GPCRs and are mainly expressed in sensory neurons of olfactory system. These form a multigene family. The PSGR subfamily is members of the olfactory receptor group. The family has limited expression in human prostate tissues and is upregulated in prostate cancer.

LGRs 4–8 are members of the rhodopsin GPCR family, which can be divided into two groups, LGRs 4, 5, and 6 and LGRs 7 and 8 according to their natural ligand. Recently, R-spondins have been identified as the ligands for LGRs 4, 5, and 6. LGRs 7 and 8 belong to relaxin family peptide (RXFP) receptors. On the basis of sequence similarity, LGRs 4, 5, and 6 are closely related to each other, showing nearly 50% identities. The three orphan receptors have a substantially large N-terminal extracellular domain (ECD) made up of 17 leucine rich repeats (LRR) (Figure 2). Lgr4, also known as Gpr48, has been reported to have a number of physiological functions by the generation of knockout mice. The loss of Lgr4 results in developmental defects in many areas, including intrauterine growth retardation associated with embryonic and perinatal lethality, abnormal renal development, ocular anterior segment dysgenesis, defective postnatal development of the male reproductive tract, impaired hair placode formation, bone formation and remodeling dysfunction, and defective development of the gall bladder and cystic ducts. Lgr5 has been shown to be a marker of hair follicle and gastrointestinal tract stem cells. Knockout of Lgr5 in mice results in total neonatal lethality accompanied with ankyloglossia and gastrointestinal distension. Lgr6 also has been proven to be a stem cell marker in hair follicles, and Lgr6-positive stem cells have been found to produce all cell lineages of the skin.

LGR subfamily GPCRs. Figure 2. LGR subfamily GPCRs.

Adhesion GPCR family

Adhesion GPCR family has a relative long N-terminal domain, which contains a number of so-called adhesion domains. These adhesion domains only existed in some adhesion molecules, such as integrins, selectins and cadherins; and the domains are thought to have adhesive properties. Another outstanding characteristic of all the Adhesion GPCRs is that there is a GPS domain linking the 7TM region to the extracellular domain, which acts as an autocatalytic site.

Because cell adhesion molecules have a crucial role in cancer progression, it is reasonable to speculate that Adhesion GPCRs also play vital functions in cancer progression and metastasis. It has been proven that Leukocyte Adhesion GPCR EMR2 is overexpressed in human breast cancer and is associated with patient survival. It has been reported that the 7TM-cadherin receptors may be involved in human cancers, such as lung cancer, gastric cancer, and melanoma. Interestingly, unlike other Adhesion GPCRs, GPR56 has been proved to suppress some cancer cell growth and metastasis by interacting with tissue transglutaminase (TG2).

GPCR and drug discovery

GPCRs remain a major source of new pharmaceuticals and the focus of extensive research efforts in academia and pharma. Recent reviews cover the structural features of the receptors and the chemical aspects of orthosteric and allosteric ligands. Among the 19 approved drug products with the greatest sales revenues at their peak year in the period up to 2013, 7 are directed toward GPCRs. The GPCR research field is advancing rapidly, and new paradigms for GPCR drug discovery must be considered in the larger context of drug discovery.

GPCR proteins are the largest single family of proteins, corresponding to 4% of those coded by the human genome. About 400 nonolfactory, human GPCRs have not yet been exploited as pharmaceutical targets. There are still 120 orphan GPCRs for which the endogenous ligand is unknown, but even for hundreds of nonorphan GPCRs untapped potential exists. Molecular modeling predictions are conducive to the deorphanizing of GPCRs. There are newly explored pharmacological parameters which will contribute to a more selective action of drugs at GPCRs. These dimensions include biased ligands, allosteric modulators, receptor antibodies, residence time, polypharmacology, and pharmacogenomics of GPCRs. Characterization of these parameters for new compounds promises to be a method of discovering more efficacious GPCR drugs with fewer side effects. Moreover, the expression pattern and physiological roles of a given GPCR can be altered in a disease state.

The canonical mode of GPCR signaling arises from activation of a receptor located on the cell surface, that is to say, to transmit an extracellular chemical signal to the cytosolic side. Nevertheless, GPCRs can signal from inside the cell or during the internalization process, and various compartments, including clathrin-coated pits and early and late endosomes, have different signaling preferences. Agonist-induced internalization of GPCRs, prior associated with desensitization has to be redefined to include active, intracellular signaling through both G-protein dependent and arrestin-dependent processes (Figure 3). In principle, through changing the physicochemical properties of a ligand, one can alter its distribution on and within the cell. A combination of transporter-, diffusion- or receptor-mediated internalization might occur. Therefore, modulation for therapeutic purposes of the processing of GPCRs within the cell and of cycling of GPCRs between endosomes and the cell surface is a yet unfulfilled concept. However, small molecular ‘pharmacoperones’ can facilitate the proper folding and trafficking to the surface of misfolded GPCRs otherwise retained in the endoplasmic reticulum.

GPCR family Figure 3. GPCR signaling can occur during the endocytic process.


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  2. Tang X L, et al. Orphan G protein-coupled receptors (GPCRs): biological functions and potential drug targets. 2012, 33(3):363-371.
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  4. Watkins H A, et al. The structure of secretin family GPCR peptide ligands: implications for receptor pharmacology and drug development. Drug Discovery Today, 2012, 17(17-18):1006-1014.
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  6. Stevens R C, et al. The GPCR Network: a large-scale collaboration to determine human GPCR structure and function. Nature Reviews Drug Discovery, 2013, 12(1):25-34.
For research use only. Not intended for any clinical use.

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