Oxidant stress influences many cellular processes, including cell growth, differentiation, and cell death. A well-recognized link between these processes and oxidant stress is via alterations in Ca(2+) signaling. However, precisely how oxidants influence Ca(2+) signaling remains unclear. Oxidant stress led to a phenotypic shift in Ca(2+) mobilization from an oscillatory to a sustained elevated pattern via calcium release-activated calcium (CRAC)-mediated capacitive Ca(2+) entry, and stromal interaction molecule 1 (STIM1)- and Orai1-deficient cells are resistant to oxidant stress. Functionally, oxidant-induced Ca(2+) entry alters mitochondrial Ca(2+) handling and bioenergetics and triggers cell death. STIM1 is S-glutathionylated at cysteine 56 in response to oxidant stress and evokes constitutive Ca(2+) entry independent of intracellular Ca(2+) stores. These experiments reveal that cysteine 56 is a sensor for oxidant-dependent activation of STIM1 and demonstrate a molecular link between oxidant stress and Ca(2+) signaling via the CRAC channel.
Recommended CitationHawkins, Brian J; Irrinki, Krishna M; Mallilankaraman, Karthik; Lien, Yu-Chin; Wang, Youjun; Bhanumathy, Cunnigaiper D; Subbiah, Ramasamy; Ritchie, Michael F; Soboloff, Jonathan; Baba, Yoshihiro; Kurosaki, Tomohiro; Joseph, Suresh K; Gill, Donald L; and Madesh, Muniswamy, "S-glutathionylation activates STIM1 and alters mitochondrial homeostasis." (2010). Department of Pathology, Anatomy, and Cell Biology Faculty Papers. Paper 126.