scholarly journals Systematic Assessment of Chemokine Signaling at Chemokine Receptors CCR4, CCR7 and CCR10

2021 ◽  
Vol 22 (8) ◽  
pp. 4232
Author(s):  
Herman D. Lim ◽  
J. Robert Lane ◽  
Meritxell Canals ◽  
Martin J. Stone
Keyword(s):  
G Protein ◽  
Chemokine Receptors ◽  
Scavenger Receptor ◽  
G Protein Signaling ◽  
Cell Trafficking ◽  
Protein Signaling ◽  
Systematic Assessment ◽  
Biased Agonism ◽  
Cc Chemokine ◽  
Stimulation Of

Chemokines interact with chemokine receptors in a promiscuous network, such that each receptor can be activated by multiple chemokines. Moreover, different chemokines have been reported to preferentially activate different signalling pathways via the same receptor, a phenomenon known as biased agonism. The human CC chemokine receptors (CCRs) CCR4, CCR7 and CCR10 play important roles in T cell trafficking and have been reported to display biased agonism. To systematically characterize these effects, we analysed G protein- and β-arrestin-mediated signal transduction resulting from stimulation of these receptors by each of their cognate chemokine ligands within the same cellular background. Although the chemokines did not elicit ligand-biased agonism, the three receptors exhibited different arrays of signaling outcomes. Stimulation of CCR4 by either CC chemokine ligand 17 (CCL17) or CCL22 induced β-arrestin recruitment but not G protein-mediated signaling, suggesting that CCR4 has the potential to act as a scavenger receptor. At CCR7, both CCL19 and CCL21 stimulated G protein signaling and β-arrestin recruitment, with CCL19 consistently displaying higher potency. At CCR10, CCL27 and CCL28(4-108) stimulated both G protein signaling and β-arrestin recruitment, whereas CCL28(1-108) was inactive, suggesting that CCL28(4-108) is the biologically relevant form of this chemokine. These comparisons emphasize the intrinsic abilities of different receptors to couple with different downstream signaling pathways. Comparison of these results with previous studies indicates that differential agonism at these receptors may be highly dependent on the cellular context.

scholarly journals Cutting Edge: Regulator of G Protein Signaling-1 Selectively Regulates Gut T Cell Trafficking and Colitic Potential

2011 ◽  
Vol 187 (5) ◽  
pp. 2067-2071 ◽  
Author(s):  
Deena L. Gibbons ◽  
Lucie Abeler-Dörner ◽  
Tim Raine ◽  
Il-Young Hwang ◽  
Anett Jandke ◽  
...  
Keyword(s):  
T Cell ◽  
G Protein ◽  
Cutting Edge ◽  
G Protein Signaling ◽  
Cell Trafficking ◽  
Protein Signaling ◽  
T Cell Trafficking

scholarly journals Identification of Critical Residues in Gα13for Stimulation of p115RhoGEF Activity and the Structure of the Gα13-p115RhoGEF Regulator of G Protein Signaling Homology (RH) Domain Complex

2011 ◽  
Vol 286 (23) ◽  
pp. 20625-20636 ◽  
Author(s):  
Nicole Hajicek ◽  
Mutsuko Kukimoto-Niino ◽  
Chiemi Mishima-Tsumagari ◽  
Christina R. Chow ◽  
Mikako Shirouzu ◽  
...  
Keyword(s):  
G Protein ◽  
G Protein Signaling ◽  
Protein Signaling ◽  
Critical Residues ◽  
Stimulation Of

scholarly journals Re-evaluating how low intrinsic efficacy and apparent bias for G protein activation relates to the improved side effect profiles of new opioid agonists

2020 ◽  
Author(s):  
Edward L. Stahl ◽  
Laura M. Bohn
Keyword(s):  
G Protein ◽  
Therapeutic Window ◽  
G Protein Signaling ◽  
Protein Signaling ◽  
Protein Activation ◽  
Biased Agonism ◽  
Intrinsic Efficacy ◽  
Cellular Environment ◽  
G Protein Activation ◽  
G Protein Coupled

AbstractIn a recent report by Gillis et al., 2020 (1), it was suggested that low intrinsic agonism, and not biased agonism, leads to an improvement in the separation of potency in opioid-induced respiratory suppression versus antinociception. Although the compounds that were tested have been shown to display G protein signaling bias in prior publications, the authors conclude that since they cannot detect biased agonism in their cellular signaling studies the compounds are therefore not biased agonists. Rather, they conclude that it is low intrinsic efficacy that leads to the therapeutic window improvement. Intrinsic efficacy is the extent to which an agonist can stimulate a G protein-coupled receptor (GPCR) response in a system. The designation of full agonist is made to compounds that produce the highest observable activation in a system (maximum intrinsic efficacy); agonists producing some fraction of that response are considered partial agonists. The maximum response window is determined by the cellular environment, receptor and effector expression levels, and the amplification readout of the system. Biased agonism takes into consideration not only intrinsic efficacy, but also potency (concentration required to reach half maximal efficacy) of an agonist in an assay. Herein, the data published in the aforementioned manuscript was used to rederive the intrinsic efficacy and bias factors as ΔΔlog(τ/KA) and ΔΔlog(Emax/EC50). Based on this reanalysis, the data does not support the conclusion that biased agonism, favoring G protein signaling, was not present. Further, these observations agree with prior studies wherein oliceridine, PZM21 and SR-17018 were first described as biased agonists with improvement in antinociception over respiratory suppression in mice. Therefore, introducing G protein signaling bias may be a means to improve opioid analgesia while avoiding certain undesirable side effects.

scholarly journals G protein signaling–biased agonism at the κ-opioid receptor is maintained in striatal neurons

2018 ◽  
Vol 11 (542) ◽  
pp. eaar4309 ◽  
Author(s):  
Jo-Hao Ho ◽  
Edward L. Stahl ◽  
Cullen L. Schmid ◽  
Sarah M. Scarry ◽  
Jeffrey Aubé ◽  
...  
Keyword(s):  
G Protein ◽  
Opioid Receptor ◽  
G Protein Signaling ◽  
Protein Signaling ◽  
Striatal Neurons ◽  
Biased Agonism

Gi-independent macrophage chemotaxis to lysophosphatidylcholine via the immunoregulatory GPCR G2A

Blood ◽  
2005 ◽  
Vol 105 (3) ◽  
pp. 1127-1134 ◽  
Author(s):  
Li V. Yang ◽  
Caius G. Radu ◽  
Li Wang ◽  
Mireille Riedinger ◽  
Owen N. Witte
Keyword(s):  
G Protein ◽  
Chemokine Receptors ◽  
Peritoneal Macrophages ◽  
Dominant Negative ◽  
Systemic Autoimmune Disease ◽  
G Protein Signaling ◽  
Protein Signaling ◽  
Biologic Effects ◽  
Macrophage Chemotaxis ◽  
G Protein Coupled

Abstract G2A is a G-protein–coupled receptor (GPCR) involved in immune regulation. Previous studies have shown that lysophosphatidylcholine (LPC), a bioactive lipid associated with atherosclerosis and autoimmunity, acts through G2A to induce diverse biologic effects. Production of LPC during cell apoptosis serves as a chemotactic signal for macrophage recruitment. Here we demonstrate that macrophage chemotaxis to LPC is dependent on G2A function. Wild-type but not G2A-deficient mouse peritoneal macrophages migrated toward LPC. RNAi-mediated knockdown of G2A in J774A.1 macrophages abolished LPC-induced chemotaxis, whereas overexpression of G2A significantly enhanced this process. Mutation of the conserved DRY motif of G2A resulted in loss of chemotaxis to LPC, suggesting a requirement for G-protein signaling. Unlike most GPCRs, including the chemokine receptors, coupling to Gi is not required for LPC/G2A-mediated chemotaxis, but coupling to Gq/11 and G12/13 is necessary as judged by inhibition with dominant negative forms of these alpha subunits or with regulators of G-protein signaling (RGS) constructs. Collectively, these data establish that pertussis toxin–insensitive G2A signaling regulates macrophage chemotaxis to LPC. Defects in this signaling pathway may be related to the pathogenesis of systemic autoimmune disease.

scholarly journals Biased agonists of the chemokine receptor CXCR3 differentially drive formation of Gαi:β-arrestin complexes

2020 ◽  
Author(s):  
Kevin Zheng ◽  
Jeffrey S. Smith ◽  
Anmol Warman ◽  
Issac Choi ◽  
Jaimee N. Gundry ◽  
...  
Keyword(s):  
Complex Formation ◽  
Signaling Pathway ◽  
G Protein ◽  
G Protein Coupled Receptors ◽  
G Protein Signaling ◽  
Protein Signaling ◽  
Gpcr Signaling ◽  
Surface Receptors ◽  
Biased Agonism ◽  
G Protein Coupled

AbstractG-protein-coupled receptors (GPCRs), the largest family of cell surface receptors, signal through the proximal effectors G proteins and β-arrestins to influence nearly every biological process. Classically, the G protein and β-arrestin signaling pathways have largely been considered separable. Recently, direct interactions between Gα protein and β-arrestin have been described and suggest a distinct GPCR signaling pathway. Within these newly described Gα:β-arrestin complexes, Gαi/o, but not other Gα protein subtypes, have been appreciated to directly interact with β-arrestin, regardless of canonical GPCR Gα protein subtype coupling. However it is unclear how biased agonists differentially regulate this newly described Gαi:β-arrestin interaction, if at all. Here we report that endogenous ligands (chemokines) of the GPCR CXCR3, CXCL9, CXCL10, and CXCL11, along with two small molecule biased CXCR3 agonists, differentially promote the formation of Gαi:β-arrestin complexes. The ability of CXCR3 agonists to form Gαi:β-arrestin complexes does not correlate well with either G protein signaling or β-arrestin recruitment. Conformational biosensors demonstrate that ligands that promoted Gαi:β-arrestin complex formation generated similar β-arrestin conformations. We find these Gαi:β-arrestin complexes can associate with CXCR3, but not with ERK. These findings further support that Gαi:β-arrestin complex formation is a distinct GPCR signaling pathway and enhance our understanding of biased agonism.

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