Abstract
Biased signaling or functional selectivity occurs when a 7TM-receptor preferentially activates one of several available pathways. It can be divided into three distinct forms: ligand bias, receptor bias, and tissue or cell bias, where it is mediated by different ligands (on the same receptor), different receptors (with the same ligand), or different tissues or cells (for the same ligand–receptor pair). Most often biased signaling is differentiated into G protein-dependent and β-arrestin-dependent signaling. Yet, it may also cover signaling differences within these groups. Moreover, it may not be absolute, i.e., full versus no activation. Here we discuss biased signaling in the chemokine system, including the structural basis for biased signaling in chemokine receptors, as well as in class A 7TM receptors in general. This includes overall helical movements and the contributions of micro-switches based on recently published 7TM crystals and molecular dynamics studies. All three forms of biased signaling are abundant in the chemokine system. This challenges our understanding of “classic” redundancy inevitably ascribed to this system, where multiple chemokines bind to the same receptor and where a single chemokine may bind to several receptors – in both cases with the same functional outcome. The ubiquitous biased signaling confers a hitherto unknown specificity to the chemokine system with a complex interaction pattern that is better described as promiscuous with context-defined roles and different functional outcomes in a ligand-, receptor-, or cell/tissue-defined manner. As the low number of successful drug development plans implies, there are great difficulties in targeting chemokine receptors; in particular with regard to receptor antagonists as anti-inflammatory drugs. Un-defined and putative non-selective targeting of the complete cellular signaling system could be the underlying cause of lack of success. Therefore, biased ligands could be the solution.
Highlights
Biased signaling or functional selectivity occurs when a 7TM-receptor preferentially activates one of several available pathways
HELICAL MOVEMENTS AND MICRO-SWITCHES INVOLVED IN CCR5 ACTIVATION OF DIFFERENT SIGNALING PATHWAYS We have recently described transmembrane residues of importance for G protein-signaling and β-arrestin binding in CCR5 [133, 134]
The experimental results discussed in this review illustrate that biased signaling is a complex phenomenon and that it exists to a large degree in the chemokine system
Summary
Biased signaling or functional selectivity occurs when a 7TM-receptor preferentially activates one of several available pathways. LIGAND BIASED SIGNALING Ligand bias describes a situation where different ligands bind the same receptor, but induce diverse responses. There is general consensus that whereas both ligands are able to activate G protein-signaling, only CCL19 induces internalization of the receptor [5, 38, 39].
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