Activation of store-operated ICRAC by hydrogen peroxide

Reactive oxygen species (ROS) such as hydrogen peroxide (H2O2) play a role in both innate immunity as well as cellular injury. H2O2 induces changes in intracellular calcium ([Ca2+](i)) in many cell types and this seems to be at least partially mediated by transient receptor potential melastatin 2 (TRPM2) in cells that express this channel. Here we show that low concentrations of H2O2 induce the activation of the Ca2+-release activated Ca2+ current I-CRAC. This effect is not mediated by direct CRAC channel activation, since H2O2 does not activate heterologously expressed CRAC channels independently of stromal interaction molecule (STIM). Instead, I-CRAC activation is partially mediated by store depletion through activation of inositol 1,4,5 trisphosphate receptors (IP3R), since pharmacological inhibition of IP3 receptors by heparin or molecular knock-out of all IP3 receptors in DT40 B cells strongly reduce H2O2-induced I-CRAC. The remainder of H2O2-induced I-CRAC activation is likely mediated by IP3R-independent store-depletion. Our data suggest that H2O2 can activate Ca2+ entry through TRPM2 as well as store-operated I-CRAC channels, thereby adding a new facet to ROS-induced Ca2+ signaling. (C) 2010 Elsevier Ltd. All rights reserved.