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Influence of Chemokine N-Terminal Modification on Biased Agonism at the Chemokine Receptor CCR1

Sanchez, Julie; Lane, Robert; Canals, Meritxell; Stone, Martin J.

Influence of Chemokine N-Terminal Modification on Biased Agonism at the Chemokine Receptor CCR1 Thumbnail


Authors

JULIE SANCHEZ JULIE.SANCHEZ@NOTTINGHAM.AC.UK
Research Fellow - Pharmacology Cell Biologist

Robert Lane

Martin J. Stone



Abstract

Leukocyte migration, a hallmark of the inflammatory response, is stimulated by the interactions between chemokines, which are expressed in injured or infected tissues, and chemokine receptors, which are G protein-coupled receptors (GPCRs) expressed in the leukocyte plasma membrane. One mechanism for the regulation of chemokine receptor signaling is biased agonism, the ability of different chemokine ligands to preferentially activate different intracellular signaling pathways via the same receptor. To identify features of chemokines that give rise to biased agonism, we studied the activation of the receptor CCR1 by the chemokines CCL7, CCL8, and CCL15(Δ26). We found that, compared to CCL15(Δ26), CCL7 and CCL8 exhibited biased agonism towards cAMP inhibition and away from β-Arrestin 2 recruitment. Moreover, N-terminal substitution of the CCL15(Δ26) N-terminus with that of CCL7 resulted in a chimera with similar biased agonism to CCL7. Similarly, N-terminal truncation of CCL15(Δ26) also resulted in signaling bias between cAMP inhibition and β-Arrestin 2 recruitment signals. These results show that the interactions of the chemokine N-terminal region with the receptor transmembrane region play a key role in selecting receptor conformations coupled to specific signaling pathways.

Citation

Sanchez, J., Lane, R., Canals, M., & Stone, M. J. (2019). Influence of Chemokine N-Terminal Modification on Biased Agonism at the Chemokine Receptor CCR1. International Journal of Molecular Sciences, 20(10), 1-15. https://doi.org/10.3390/ijms20102417

Journal Article Type Article
Acceptance Date May 9, 2019
Online Publication Date May 15, 2019
Publication Date May 15, 2019
Deposit Date May 28, 2019
Publicly Available Date Mar 29, 2024
Journal International Journal of Molecular Sciences
Print ISSN 1661-6596
Electronic ISSN 1422-0067
Publisher MDPI
Peer Reviewed Peer Reviewed
Volume 20
Issue 10
Article Number 2417
Pages 1-15
DOI https://doi.org/10.3390/ijms20102417
Keywords chemokine; chemokine receptor; chemokine receptor 1 (CCR1); G protein-coupled receptor (GPCR); binding; receptor activation; biased agonism
Public URL https://nottingham-repository.worktribe.com/output/2099806
Publisher URL https://www.mdpi.com/1422-0067/20/10/2417

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