Biased signalling: the instinctive skill of the cell in the selection of appropriate signalling pathways.
GPCRs (G-protein-coupled receptors) are members of a family of proteins which are generally regarded as the largest group of therapeutic drug targets. Ligands of GPCRs do not usually activate all cellular signalling pathways linked to a particular seven-transmembrane receptor in a uniform manner. The fundamental idea behind this concept is that each ligand has its own ability, while interacting with the receptor, to activate different signalling pathways (or a particular set of signalling pathways) and it is this concept which is known as biased signalling. The importance of biased signalling is that it may selectively activate biological responses to favour therapeutically beneficial signalling pathways and to avoid adverse effects. There are two levels of biased signalling. First, bias can arise from the ability of GPCRs to couple to a subset of the available G-protein subtypes: Gαs, Gαq/11, Gαi/o or Gα12/13. These subtypes produce the diverse effects of GPCRs by targeting different effectors. Secondly, biased GPCRs may differentially activate G-proteins or β-arrestins. β-Arrestins are ubiquitously expressed and function to terminate or inhibit classic G-protein signalling and initiate distinct β-arrestin-mediated signalling processes. The interplay of G-protein and β-arrestin signalling largely determines the cellular consequences of the administration of GPCR-targeted drugs. In the present review, we highlight the particular functionalities of biased signalling and discuss its biological effects subsequent to GPCR activation. We consider that biased signalling is potentially allowing a choice between signalling through 'beneficial' pathways and the avoidance of 'harmful' ones.
Faculty of Life Science and Technology, Kunming University of Science and Technology, Kunming, Yunnan, 650500, China.
Ying
Y
Liu
Faculty of Life Science and Technology, Kunming University of Science and Technology, Kunming, Yunnan, 650500, China.
Yang
Y
Yang
Molecular Pharmacology Group, Institute of Molecular, Cell and Systems Biology, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8QQ, Scotland, U.K.
Richard
R
Ward
Faculty of Life Science and Technology, Kunming University of Science and Technology, Kunming, Yunnan, 650500, China.
Su
S
An
Faculty of Life Science and Technology, Kunming University of Science and Technology, Kunming, Yunnan, 650500, China.
Xiao-Xi
XX
Guo
Department of Urology, the People's Hospital of Yunnan Province, Kunming, Yunnan, 650032, China lw13908701155@163.com xtrgfq@homail.com.
Wei
W
Li
Faculty of Life Science and Technology, Kunming University of Science and Technology, Kunming, Yunnan, 650500, China lw13908701155@163.com xtrgfq@homail.com.
Tian-Rui
TR
Xu
D000818:Animals; D019390:Arrestins / Q000378:metabolism; D019204:GTP-Binding Proteins / Q000378:metabolism; D006801:Humans; D008024:Ligands; D011487:Protein Conformation; D018035:Receptors, Odorant / Q000737:chemistry / Q000378:metabolism*; D015398:Signal Transduction; D000071557:beta-Arrestins
D019390:Arrestins; D008024:Ligands; D018035:Receptors, Odorant; D000071557:beta-Arrestins; C077170:G-protein coupled receptor OR3; D019204:GTP-Binding Proteins
G-protein-coupled receptors (GPCRs); biased signalling; drug discovery; ligands; β-arrestin