1. Hypoxia-induced Acidosis Uncouples the STIM-Orai Calcium Signaling Complex
- Author
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Xiang D. Tang, Karthik Mallilankaraman, Xiaoxiang Deng, Youjun Wang, Reynold A. Panettieri, Donald L. Gill, Salvatore Mancarella, Muniswamy Madesh, Gavin Landesberg, and Rosario Scalia
- Subjects
inorganic chemicals ,ORAI1 Protein ,Myocytes, Smooth Muscle ,Biology ,Biochemistry ,medicine ,Humans ,Myocyte ,Calcium Signaling ,Stromal Interaction Molecule 1 ,Molecular Biology ,Ion channel ,Calcium signaling ,ORAI1 ,Endoplasmic reticulum ,Membrane Proteins ,STIM1 ,Cell Biology ,Hypoxia (medical) ,Cell Hypoxia ,Neoplasm Proteins ,Cell biology ,Protein Transport ,Cytosol ,HEK293 Cells ,Intercellular Junctions ,Multiprotein Complexes ,Calcium ,Calcium Channels ,medicine.symptom ,Signal Transduction - Abstract
The endoplasmic reticulum Ca(2+)-sensing STIM proteins mediate Ca(2+) entry signals by coupling to activate plasma membrane Orai channels. We reveal that STIM-Orai coupling is rapidly blocked by hypoxia and the ensuing decrease in cytosolic pH. In smooth muscle cells or HEK293 cells coexpressing STIM1 and Orai1, acute hypoxic conditions rapidly blocked store-operated Ca(2+) entry and the Orai1-mediated Ca(2+) release-activated Ca(2+) current (I(CRAC)). Hypoxia-induced blockade of Ca(2+) entry and I(CRAC) was reversed by NH(4)(+)-induced cytosolic alkalinization. Hypoxia and acidification both blocked I(CRAC) induced by the short STIM1 Orai-activating region. Although hypoxia induced STIM1 translocation into junctions, it did not dissociate the STIM1-Orai1 complex. However, both hypoxia and cytosolic acidosis rapidly decreased Förster resonance energy transfer (FRET) between STIM1-YFP and Orai1-CFP. Thus, although hypoxia promotes STIM1 junctional accumulation, the ensuing acidification functionally uncouples the STIM1-Orai1 complex providing an important mechanism protecting cells from Ca(2+) overload under hypoxic stress conditions.
- Published
- 2011
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