Biased and G Protein-Independent Signaling of Chemokine Receptors

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.

i-bodies, Human Single Domain Antibodies That Antagonize Chemokine Receptor CXCR4

“…Graphs were derived by combining the mean from each replicate data point (from either 1, 2, or 3 experiments) into one figure. IC 50 values were derived by fitting a curve to each individual experiment and then obtaining the mean and standard deviation from the combined IC 50 values.…”

“…AM3-114 showed dose-dependent but variable binding to all cell lines, except HL-60 where little binding was observed. The variable binding is perhaps a function of the observation that GPCR conformation and tissue/cell type can markedly affect ligand binding and activity (49,50).…”

“…It has been postulated that chemokine receptors such as CXCR4 can preferentially activate one of several possible signaling pathways, a concept termed biased signaling or functional selectivity (49,50). Consequently, there is increasing interest in developing GPCR-specific drugs with novel modalities that are capable of modulating one GPCR signaling pathway over another in a biased manner.…”

Antibody Neutralization of CXCL10 in Vivo Is Dependent on Binding to Free and Not Endothelial-bound Chemokine

“…Indeed, the majority of chemokines are able to bind to several chemokine receptors, and receptors can often be activated by various ligands, leading to the hypothesis that the inhibition of one single chemokine or receptor is not sufficient to observe beneficial clinical effects. However, data are currently accumulating to demonstrate that the chemokine system is not redundant in terms of signal cascades as well as in the temporal and spatial patterns of expression in vivo (24). Recently it has been shown that the ligands for CXCR3 induce different effects.…”

Activated Microglia in the Brain: Mitochondrial and Cell Membrane-Associated Targets for Positron Emission Tomography

“…Maciejewski-Lenoir et al [111] Steen et al [112] made the promiscuity of chemokine receptors for several peptide ligands responsible for the difficulties to develop effective small-molecule therapeutics targeting chemokine receptors. With regard to only one endogenous ligand, the CX3CR1 receptor provides better prerequisites than the most other chemokine receptors.…”