Biased receptor functionality versus biased agonism in G-protein-coupled receptors

Abstract

Functional selectivity is a property of G-protein-coupled receptors (GPCRs) by which activation by different agonists leads to different signal transduction mechanisms. This phenomenon is also known as biased agonism and has attracted the interest of drug discovery programs in both academy and industry. This relatively recent concept has raised concerns as to the validity and real translational value of the results showing bias; firstly biased agonism may vary significantly depending on the cell type and the experimental constraints, secondly the conformational landscape that leads to biased agonism has not been defined. Remarkably, GPCRs may lead to differential signaling even when a single agonist is used. Here we present a concept that constitutes a biochemical property of GPCRs that may be underscored just using one agonist, preferably the endogenous agonist. 'Biased receptor functionality' is proposed to describe this effect with examples based on receptor heteromerization and alternative splicing. Examples of regulation of final agonist-induced outputs based on interaction with β-arrestins or calcium sensors are also provided. Each of the functional GPCR units (which are finite in number) has a specific conformation. Binding of agonist to a specific conformation, i.e. GPCR activation, is sensitive to the kinetics of the agonist-receptor interactions. All these players are involved in the contrasting outputs obtained when different agonists are assayed.