Functional Selectivity and Biased Receptor Signaling

Abstract

With the emergence of information describing functional selectivity and biased agonists and antagonists has come a lack of confidence in "one size fits all" assays for detection of agonism. Seven-transmembrane receptors are pleiotropic with respect to the signaling protein to which they couple in a cell, and many conformations of the receptor can be formed; this leads to systems where ligands can stabilize unique conformations that go on to selectively activate signaling pathways. Thus, such "biased" ligands can produce cell-specific agonism that may require targeted assays to detect and quantify. It also predicts that ligands can have many different efficacies for the many behaviors that the receptor can exhibit (referred to as "pluridimensional efficacy"), leading to a breakdown in the common classifications of agonist and antagonist. This all poses unique challenges to the pharmacologic nomenclature of drugs, the detection and optimization of new drugs, and the association of phenotypic clinical profiles with pharmacological properties of drugs.

G protein-coupled receptor-receptor interactions give integrative dynamics to intercellular communication

“…Members of this superfamily are encoded by 4% of all genes and contribute to a variety of physiologic processes in mammals (Lefkowitz, 2007). Their signaling as monomeric units has been well characterized in several different experimental contexts (Chabre and le Maire, 2005;Kenakin, 2011).…”

“…Furthermore, signaling from GPCR monomers is characterized by an intrinsic plasticity, as GPCR activation can result in different patterns of signal transduction, such as G protein and/or arrestin pathways (Zidar et al, 2009). The concept of biased GPCR agonism, meaning functional selectivity, was developed by Kenakin (2011). The agonist stabilization of distinct active states in receptor conformation was suggested to be the mechanism involved in producing the activation of discrete signal transduction pathways by GPCR.…”

G Protein–Coupled Receptor Endocytosis Confers Uniformity in Responses to Chemically Distinct Ligands

“…Over the past couple of decades, however, experimental evidence has accumulated, indicating the existence of remarkable diversity in GPCR activation states and the effects of chemically distinct ligands. Now it is widely recognized that there are multiple sources of functional diversity at GPCRs, involving not only equilibrium affinity and intrinsic efficacy of the drug, but also kinetics of the drug-GPCR interaction and an extended theoretical formulation of intrinsic efficacy that is now called functional selectivity or agonist bias (Kenakin, 2011).…”

Agonism, Antagonism, and Inverse Agonism Bias at the Ghrelin Receptor Signaling

“…Therefore, development of biased ligands that will selectively inhibit or activate only one or a subset of the GHS-R1a-dependent physiological responses could have significant therapeutic advantages. This aim is certainly now attainable because during the last decade many independent studies on GPCRs have described biased agonists that are selective of a given downstream signaling pathway (14,15). Unlike the endogenous ligand that usually activates all the G protein and ␤-arrestin-dependent pathways, the synthetic ligands could thus selectively activate only some of them, for instance activation of ␤-arrestin with no effect on G proteins (16).…”