Activation of store-operated I(CRAC) 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 ([Ca(2+)]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 Ca(2+)-release activated Ca(2+) 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 Ca(2+) entry through TRPM2 as well as store-operated CRAC channels, thereby adding a new facet to ROS-induced Ca(2+) signaling.
Grupe
Morten
M
Laboratory of Cell and Molecular Signaling, Center for Biomedical Research at The Queen's Medical Center and John A. Burns School of Medicine at the University of Hawaii, 1301 Punchbowl St., Honolulu, HI 96813, USA.
Myers
George
G
Penner
Reinhold
R
Fleig
Andrea
A
D015220:Calcium Channels / Q000187:drug effects / Q000502:physiology*; D020013:Calcium Signaling / Q000187:drug effects / Q000502:physiology*; D057809:HEK293 Cells; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology*; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000502:physiology*; D019169:Jurkat Cells; D007811:Lanthanum / Q000494:pharmacology; D000071740:ORAI1 Protein; D018408:Patch-Clamp Techniques; D050053:TRPM Cation Channels / Q000187:drug effects / Q000502:physiology
D015220:Calcium Channels; D053496:Inositol 1,4,5-Trisphosphate Receptors; D000071740:ORAI1 Protein; C510746:ORAI1 protein, human; D050053:TRPM Cation Channels; C121934:TRPM2 protein, human; D007811:Lanthanum; D006861:Hydrogen Peroxide