The anti-inflammatory agent flufenamic acid depresses store-operated channels by altering mitochondrial calcium homeostasis

Abstract Fenamates like flufenamic acid (FFA) are anti-inflammatory drugs known to alter ion fluxes through the plasma membrane. They are for instance potent blockers of cation and anion channels, and FFA is now commonly used to block currents through TRP channels and receptor-operated channels. However, FFA exerts complex and multifaceted actions on ion transport systems and, in most instances, a molecular understanding of these FFA-dependent modulations is lacking. In addition, FFA is also to known to perturb the homeostasis of Ca 2+ . In the present report, we investigated whether the FFA-induced alterations of the Ca 2+ homeostasis could play a role in the FFA-dependent modulation of transmembrane ion fluxes. Experiments performed with the Ca 2+ indicator Fluo-4 on cultured cortical neurons and HEK-293 cells showed that FFA increased the cytosolic concentration of Ca 2+ even in cells kept in a Ca 2+ -free medium or when the endoplasmic reticulum was depleted with thapsigargin. The FFA-dependent Ca 2+ responses were, however, strongly reduced by bongkrekic acid, a specific ligand of the mitochondrial ADP/ATP carrier which, in addition, inhibits the permeability transition pore. Like FCCP, FFA released Ca 2+ from isolated brain mitochondria and indirectly modulates store-operated Ca 2+ channels. We suggest that some of the effects of FFA on plasma membrane ion channels could be explained, at least partially, by its ability to modulate the mitochondrial Ca 2+ homeostasis.