The anti-inflammatory agent flufenamic acid depresses store-operated channels by altering mitochondrial calcium homeostasis.
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 Ca2+. In the present report, we investigated whether the FFA-induced alterations of the Ca2+ homeostasis could play a role in the FFA-dependent modulation of transmembrane ion fluxes. Experiments performed with the Ca2+ indicator Fluo-4 on cultured cortical neurons and HEK-293 cells showed that FFA increased the cytosolic concentration of Ca2+ even in cells kept in a Ca2+-free medium or when the endoplasmic reticulum was depleted with thapsigargin. The FFA-dependent Ca2+ 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 Ca2+ from isolated brain mitochondria and indirectly modulates store-operated Ca2+ 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 Ca2+ homeostasis.
Tu
Peng
P
UMR CNRS 5249, Grenoble, France.
Brandolin
Gérard
G
Bouron
Alexandre
A
D000814:Aniline Compounds; D000818:Animals; D000831:Animals, Newborn; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D002118:Calcium / Q000502:physiology*; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D015220:Calcium Channels / Q000502:physiology*; D002462:Cell Membrane / Q000502:physiology; D002478:Cells, Cultured; D005439:Flufenamic Acid / Q000494:pharmacology*; D005456:Fluorescent Dyes; D006706:Homeostasis; D006801:Humans; D066298:In Vitro Techniques; D053078:Membrane Potential, Mitochondrial; D051379:Mice; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D014966:Xanthenes
D000814:Aniline Compounds; D000894:Anti-Inflammatory Agents, Non-Steroidal; D002121:Calcium Channel Blockers; D015220:Calcium Channels; C409648:Fluo 4; D005456:Fluorescent Dyes; D014966:Xanthenes; D005439:Flufenamic Acid; D002118:Calcium