β-arrestin-based receptor signaling paradigms: potential therapeutic targets for complex age-related disorders
- 1University of Antwerp, Belgium
- 2Center for Molecular Neurology, University of Antwerp, Belgium
- 3Humboldt-Universität zu Berlin, Germany
- 4Medical University of South Carolina, United States
- 5Division of Endocrinology, Diabetes and Medical genetics, MUSC Health, United States
G protein-coupled receptors (GPCRs) were first characterized as signal transducers that elicit downstream effects through modulation of guanine (G) nucleotide-binding proteins. The pharmacotherapeutic exploitation of this signaling paradigm has created a drug-based field covering nearly 50% of the current pharmacopeia. Since the groundbreaking discoveries of the late 1990s to the present day, it is now clear however that GPCRs can also generate productive signaling cascades through the modulation of β-arrestin functionality. β-arrestins were first thought to only regulate receptor desensitization and internalization – exemplified by the action of visual arrestin with respect to rhodopsin desensitization. Nearly 20 years ago it was found that rather than controlling GPCR signal termination, productive β-arrestin dependent GPCR signaling paradigms were highly dependent on multi-protein complex formation and generated long-lasting cellular effects, in contrast to G protein signaling which is transient and functions through soluble second messenger systems. β-arrestin signaling was then first shown to activate mitogen activated protein (MAP) kinase signaling in a G protein-independent manner and eventually initiate protein transcription - thus controlling expression patterns of downstream proteins. While the possibility of developing β-arrestin biased or functionally selective ligands is now being investigated, no additional research has been performed on its possible contextual specificity in treating age-related disorders. The ability of β-arrestin-dependent signaling to control complex and multidimensional protein expression patterns makes this therapeutic strategy feasible, as treating complex age-related disorders will likely require therapeutics that can exert network-level efficacy profiles. It is our understanding that therapeutically targeting G protein-independent effectors such as β-arrestin will aid in the development of precision medicines with tailored efficacy profiles for disease/age-specific contextualities.
Keywords: beta-arrestin signaling, Ligand bias, GPCRs (G protein-coupled receptors), age-related disorders, Precision, tailored efficacy
Received: 22 Aug 2018;
Accepted: 07 Nov 2018.
Edited by:Salvatore Salomone, Università degli Studi di Catania, Italy
Reviewed by:Philippe Rondard, Centre national de la recherche scientifique (CNRS), France
Bice Chini, Italian National Research Council, Italy
Ada Girnita, Karolinska Institutet (KI), Sweden
Copyright: © 2018 van Gastel, Hendrickx, Leysen, Santos-Otte, Luttrell and Maudsley. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Prof. Stuart Maudsley, University of Antwerp, Antwerp, Belgium, Stuart.Maudsley@uantwerpen.vib.be