Dataset Information

Adaptation and Constraint in the Atypical Chemokine Receptor Family in Mammals.

ABSTRACT: Atypical chemokine receptors (ACKRs) are a subclass of G protein-coupled receptors characterized by promiscuity of ligand binding and an obvious inability to signal after ligand binding. Although some discoveries regarding this family in Homo sapiens and other species have been reported in some studies, the evolution and function of multiple ACKR in mammals have not yet been clearly understood. We performed an evolutionary analysis of ACKR genes (ACKR1, ACKR2, ACKR3, and ACKR4) in mammals. Ninety-two full-length ACKR genes from 27 mammal species were retrieved from the Genbank and Ensemble databases. Phylogenetic analysis showed that there were four well-conserved subfamilies in mammals. Synteny analysis revealed that ACKR genes formed conserved linkage groups with their adjacent genes across mammalian species, facilitating the identification of ACKRs in as yet unannotated genome datasets. Analysis of the site-specific profiles established by posterior probability revealed the positive-selection sites to be distributed mainly in the ligand binding region of ACKR1. This study highlights the molecular evolution of the ACKR gene family in mammals and identifies the critical amino acid residues likely to be relevant to ligand binding. Further experimental verification of these findings may provide valuable information regarding the ACKR's biochemical and physiological functions.

SUBMITTER: Pan L

PROVIDER: S-EPMC6174752 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Publications

Adaptation and Constraint in the Atypical Chemokine Receptor Family in Mammals.

Pan Li L Lv Jianliang J Zhang Zhongwang Z Zhang Yongguang Y

BioMed research international 20180924

Atypical chemokine receptors (ACKRs) are a subclass of G protein-coupled receptors characterized by promiscuity of ligand binding and an obvious inability to signal after ligand binding. Although some discoveries regarding this family in Homo sapiens and other species have been reported in some studies, the evolution and function of multiple ACKR in mammals have not yet been clearly understood. We performed an evolutionary analysis of ACKR genes (ACKR1, ACKR2, ACKR ...[more]

PMID: 30345310

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Project description:We observed in PRESTO-Tango β-arrestin recruitment assays that the α1-adrenergic receptor (AR) antagonist prazosin activates chemokine (C-X-C motif) receptor (CXCR)4. This prompted us to further examine this unexpected pharmacological behavior. We screened a panel of 14 α1/2- and β1/2/3-AR antagonists for CXCR4 and atypical chemokine receptor (ACKR)3 agonist activity in PRESTO-Tango assays against the cognate agonist CXCL12. We observed that multiple α1-AR antagonists activate CXCR4 (CXCL12 = prazosin = cyclazosin > doxazosin) and ACKR3 (CXCL12 = prazosin = cyclazosin > alfuzosin = doxazosin = phentolamine > terazosin = silodosin = tamsulosin). The two strongest CXCR4/ACKR3 activators, prazosin and cyclazosin, were selected for a more detailed evaluation. We found that the drugs dose-dependently activate both receptors in β-arrestin recruitment assays, stimulate ERK1/2 phosphorylation in HEK293 cells overexpressing each receptor, and that their effects on CXCR4 could be inhibited with AMD3100. Both α1-AR antagonists induced significant chemical shift changes in the 1H-13C-heteronuclear single quantum correlation spectrum of CXCR4 and ACKR3 in membranes, suggesting receptor binding. Furthermore, prazosin and cyclazosin induced internalization of endogenous CXCR4/ACKR3 in human vascular smooth muscle cells (hVSMC). While these drugs did not in induce chemotaxis in hVSMC, they inhibited CXCL12-induced chemotaxis with high efficacy and potency (IC50: prazosin-4.5 nM, cyclazosin 11.6 pM). Our findings reveal unexpected pharmacological properties of prazosin, cyclazosin, and likely other α1-AR antagonists. The results of the present study imply that prazosin and cyclazosin are biased or partial CXCR4/ACKR3 agonists, which function as potent CXCL12 antagonists. Our findings could provide a mechanistic basis for previously observed anti-cancer properties of α1-AR antagonists and support the concept that prazosin could be re-purposed for the treatment of disease processes in which CXCR4 and ACKR3 are thought to play significant pathophysiological roles, such as cancer metastases or various autoimmune pathologies.

Dataset Information

Adaptation and Constraint in the Atypical Chemokine Receptor Family in Mammals.

Publications

Adaptation and Constraint in the Atypical Chemokine Receptor Family in Mammals.

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