GPCRs: The most promiscuous druggable receptor of the mankind

Abstract

All physiological events in living organisms originated as specific chemical/biochemical signals on the cell surface and transmitted into the cytoplasm. This signal is translated within milliseconds-hours to a specific and unique order required to maintain optimum performance and homeostasis of living organisms. Examples of daily biological functions include neuronal communication and neurotransmission in the process of learning and memory, secretion (hormones, sweat, and saliva), muscle contraction, cellular growth, differentiation and migration during wound healing, and immunity to fight infections. Among the different transducers for such life-dependent signals is the large family of G protein-coupled receptors (GPCRs). GPCRs constitute roughly 800 genes, corresponding to 2% of the human genome. While GPCRs control a plethora of pathophysiological disorders, only approximately one-third of GPCR families have been deorphanized and characterized. Recent drug data show that around 40% of the recommended drugs available in the market target mainly GPCRs. In this review, we presented how such system signals, either through G protein or via other players, independent of G protein, function within the biological system. We also discussed drugs in the market or clinical trials targeting mainly GPCRs in various diseases, including cancer.

Keywords: AC, Adenylyl Cyclase; Arrestin; CCR, Chemokine Receptor; COX, Cyclooxygenase; DAG, Diacylglycerol; Drugs; ERK, Extracellular signal-Regulated Kinase; G proteins; GIP, Gastric Inhibitory Peptide; GLP1R, Glucagon-Like Peptide-1 Receptor; GPCR; GRKs; GRKs, G protein-coupled Receptor Kinases; Heterodimerization; IP3, Inositol 1,4,5-triphosphate; MAPK, Mitogen-Activated Protein Kinase; NMDA, N-Methyl D-Aspartate; Nbs, Nanobodies; PAR-1, Protease Activated Receptor 1; PIP2, Phosphatidylinositol-4,5-bisphosphate; PKA, Protein Kinase A; Signaling; cAMP, cyclic AMP.

Fig. 1

Flowchart showing the classification of GPCRs superfamily. Approximately 826 GPCRs members can be classified into five classes according to seven-transmembrane domain sequence homology (Fredriksson et al., 2003, Langenhan, 2020).

Fig. 2

Schematic diagram of GPCRs signaling steps, A)- G protein-dependent signaling; Following binding of agonist to the extracellular domain of receptor results in conformation change of receptor including cytosolic c-Terminus leading to recruit specific heterotrimeric G protein. Exchange of GDP by GTP of Gα subunit (Gαq, Gαs, Gαi, and Gα12/13) results in dissociation of heterotrimeric G proteins and downstream signaling of Gα from βγ. B)- G protein independent signaling; Following termination of first wave signals by PKC, PKA, or GRKs that lead to β-Arrestins recruitment to c-terminus of the receptor. β-Arrestins will prevent further G proteins coupling, facilitate internalization of receptor and act as a scaffold for MAP kinase signaling as a second signal wave.