Mechanisms of signalling and biased agonism in G protein-coupled receptors

Abstract

G protein-coupled receptors (GPCRs) are the largest group of cell surface receptors in humans that signal in response to diverse inputs and regulate a plethora of cellular processes. Hence, they constitute one of the primary drug target classes. Progress in our understanding of GPCR dynamics, activation and signalling has opened new possibilities for selective drug development. A key advancement has been provided by the concept of biased agonism, which describes the ability of ligands acting at the same GPCR to elicit distinct cellular signalling profiles by preferentially stabilizing different active conformational states of the receptor. Application of this concept raises the prospect of 'designer' biased agonists as optimized therapeutics with improved efficacy and/or reduced side-effect profiles. However, this application will require a detailed understanding of the spectrum of drug actions and a structural understanding of the drug-receptor interactions that drive distinct pharmacologies. The recent revolution in GPCR structural biology provides unprecedented insights into ligand binding, conformational dynamics and the control of signalling outcomes. These insights, together with new approaches to multi-dimensional analysis of drug action, are allowing refined classification of drugs according to their pharmacodynamic profiles, which can be linked to receptor structure and predictions of preclinical drug efficacy.

Biased M1positive allosteric modulators reveal novel role of phospholipase D in M1-dependent rodent cortical plasticity

“…3A) (13,19,30). Similar to previous findings, bath application of the non-biased M1 PAM VU0453595 for 10 min before and during CCh application leads to a robust LTD ( Theoretically, M1 PAMs that confer this form of biased M1 signaling stabilize a conformation of M1 that favors activation of signaling by PLC and not PLD (43)(44)(45)(46). Based on this, if these PAMs confer true bias to M1 signaling, they should inhibit PLD-mediated responses.…”

Kinetics of cytokine receptor trafficking determine signaling and functional selectivity

“…G-protein-coupled receptors (GPCRs), which contain seven-transmembrane domains, are the classical system where biased signaling was first described (Hilger et al, 2018;Wootten et al, 2018). In this system, different ligands binding a common receptor can trigger differential signaling programs by instructing specifics allosteric changes in the transmembrane a-helices of the receptor (Hilger et al, 2018;Wootten et al, 2018). However, although elegant, this mechanism cannot be applied to the family of single-spanning transmembrane domain cytokine receptors.…”

Recent achievements in developing selective Gq inhibitors

“…In contrast to GPCRs, the role of modulating G proteins is much less understood in biased GPCRs signaling pathways, which, to a large degree, is due to lack of selective and potent modulators of G proteins. Biased GPCR signaling pathways have been explored within the context of biased ligands, which induce distinct GPCR conformations that allow selective coupling to effectors and produce distinct physiological outcomes and three‐dimensional (3D) structure subtypes …”

“…Biased GPCR signaling pathways have been explored within the context of biased ligands, which induce distinct GPCR conformations that allow selective coupling to effectors and produce distinct physiological outcomes. 44,45 The selective regulation of different G protein subtypes remains challenging due to the fact that G proteins are located intracellularly and generally have high similarity, both in terms of the sequence alignment 40 and three-dimensional (3D) structure subtypes. 22,[46][47][48] Only very few compounds are available that can modulate G protein activity, including the bacterial proteins, pertussis toxin and cholera toxin, 49,50 which have long been known to enzymatically modulate G i and G s proteins, respectively.…”