Location Bias as Emerging Paradigm in GPCR Biology and Drug Discovery

Abstract

GPCRs are the largest receptor family that are involved in virtually all biological processes. Pharmacologically, they are highly druggable targets, as they cover more than 40% of all drugs in the market. Our knowledge of biased signaling provided insight into pharmacology vastly improving drug design to avoid unwanted effects and achieve higher efficacy and selectivity. However, yet another feature of GPCR biology is left largely unexplored, location bias. Recent developments in this field show promising avenues for evolution of new class of pharmaceuticals with greater potential for higher level of precision medicine. Further consideration and understanding of this phenomenon with deep biochemical and molecular insights would pave the road to success. In this review, we critically analyze this perspective and discuss new avenues of investigation.

Keywords: Biological Science; Cell Biology; Molecular Biology; Pharmacology.

Graphical abstract

Figure 1

PM and Subcellular Organelle Localization and Signaling of GPCRs A schematic representation of GPCR cycle and different GPCRs in various cellular organelles. (A) A GPCR in its inactive confirmation coupled with heterotrimeric G proteins. (B) Ligand binding to GPCR induces conformational changes releasing heterotrimeric G proteins. Various downstream signaling cascades are activated depending on the specific subfamily of each G protein. (C) Ligand-bound GPCR attracts GRKs, which phosphorylate the receptor initiating their signal termination process through interaction with β-arrestins and endosomal entry. (D) The proposed model for conformation of GPCR in the outer and inner nuclear membranes. (E) F2rl1 is an example of a nuclear GPCR that translocates to the nucleus upon activation and induces Vegfa transcription through interaction with Sp1 transcriptional factor. (F) mGlu₅, another example of a nuclear GPCR initiates downstream signaling inside the nucleus. (G) Activation of PM AT₁R leads to phosphorylation of nuclear pore, which in turn facilitates its nuclear translocation. (H) GPR30 is an example of ER resident GPCR, which initiates downstream signaling within the ER network. (I) β₁AR is an example of Golgi apparatus GPCR initiates downstream signaling inside the Golgi lumen. (J) NK₁R is an example of endosome-located active GPCR which displays physiological output location bias from endosomal signaling. The receptor could also go through lysosomal degradation or recycle to PM as part of GPCR life cycle. (K) MT₁ is an example of mitochondrial resident GPCR, which initiates downstream signaling inside the mitochondria.