The
adenosine 5'-triphosphate (
ATP)-gated
P2X7 receptor is a membrane-bound, non-selective
cation channel, expressed in a variety of cell types. The P2X7 senses high extracellular
ATP concentrations and seems to be implicated in a wide range of cellular functions as well as pathophysiological processes, including immune responses and
inflammation, release of gliotransmitters and
cytokines,
cancer cell growth or development of
neurodegenerative diseases. In the present study, we identified natural compounds and analogues that can block or sensitize the
ATP (1 mM)-induced Ca(2+) response using a HEK293 cell line stably expressing human P2X7 and fluorometric imaging plate reader technology. For instance,
teniposide potently blocked the human P2X7 at sub-miromolar concentrations, but not human P2X4 or rat P2X2. A marked block of
ATP-induced Ca(2+) entry and
Yo-Pro-1 uptake was also observed in human A375
melanoma cells and mouse microglial cells, both expressing P2X7. On the other hand, agelasine (AGL) and garcinolic
acid (GA) facilitated the P2X7 response to
ATP in all three cell populations. GA also enhanced the
YO-PRO-1 uptake, whereas AGL did not affect the
ATP-stimulated intracellular accumulation of this
dye. According to the pathophysiological role of P2X7 in various diseases, selective modulators may have potential for further development, e.g. as neuroprotective or
antineoplastic drugs.