期刊
BIOMOLECULES
卷 12, 期 9, 页码 -出版社
MDPI
DOI: 10.3390/biom12091309
关键词
P2X7 receptor; P2X4 receptor; P2Y receptor; purinergic signalling; amiloride; T cell; B cell; monocyte; interleukin-1 beta; low affinity IgE receptor
资金
- Australian Government Research Training Program Scholarships
6-FPHMA is identified as a novel P2X7 antagonist that can inhibit P2X7 from multiple species. However, its poor selectivity excludes it from being used as a specific P2X7 antagonist.
P2X7 is an extracellular adenosine 5'-triphopshate (ATP)-gated cation channel present on leukocytes, where its activation induces pro-inflammatory cytokine release and ectodomain shedding of cell surface molecules. Human P2X7 can be partially inhibited by amiloride and its derivatives at micromolar concentrations. This study aimed to screen a library of compounds derived from amiloride or its derivative 5-(N,N-hexamethylene) amiloride (HMA) to identify a potential P2X7 antagonist. 6-Furopyridine HMA (6-FPHMA) was identified as a novel P2X7 antagonist and was characterized further. 6-FPHMA impaired ATP-induced dye uptake into human RPMI8226 multiple myeloma cells and human P2X7-HEK293 cells, in a concentration-dependent, non-competitive manner. Likewise, 6-FPHMA blocked ATP-induced Ca2+ fluxes in human P2X7-HEK293 cells in a concentration-dependent, non-competitive manner. 6-FPHMA inhibited ATP-induced dye uptake into human T cells, and interleukin-113 release within human blood and CD23 shedding from RPMI8226 cells. 6-FPHMA also impaired ATP-induced dye uptake into murine P2X7- and canine P2X7-HEK293 cells. However, 6-FPHMA impaired ATP-induced Ca2+ fluxes in human P2X4-HEK293 cells and non-transfected HEK293 cells, which express native P2Y(1), P2Y(2) and P2Y(4). In conclusion, 6-FPHMA inhibits P2X7 from multiple species. Its poor selectivity excludes its use as a specific P2X7 antagonist, but further study of amiloride derivatives as P2 receptor antagonists is warranted.
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