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Reduced SERCA activity underlies dysregulation of Ca 2+ homeostasis under atmospheric O 2 levels
Author(s) -
Keeley Thomas P.,
Siow Richard C. M.,
Jacob Ron,
Mann Giovanni E.
Publication year - 2018
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.201700685rrr
Subject(s) - homeostasis , serca , chemistry , medicine , biophysics , biology , biochemistry , atpase , enzyme
Unregulated increases in cellular Ca 2+ homeostasis are a hallmark of pathophysiological conditions and a key trigger of cell death. Endothelial cells cultured under physiologic O 2 conditions (5% O 2 ) exhibit a reduced cytosolic Ca 2+ response to stimulation. The mechanism for reduced plateau [Ca 2+ ] i upon stimulation was due to increased sarco/endoplasmic reticulum Ca 2+ ATPase (SERCA)‐mediated reuptake rather than changes in Ca 2+ influx capacity. Agonist‐stimulated phosphorylation of the SERCA regulatory protein phospholamban was increased in cells cultured under 5% O 2 . Elevation of cytosolic and mitochondrial [Ca 2+ ] and cell death after prolonged ionomycin treatment, as a model of Ca 2+ overload, were lower when cells were cultured long‐term under 5% compared with 18% O 2 . This protection was abolished by cotreatment with the SERCA inhibitor cyclopiazonic acid. Taken together, these results demonstrate that culturing cells under hyperoxic conditions reduces their ability to efficiently regulate [Ca 2+ ]i, resulting in greater sensitivity to cytotoxic stimuli.—Keeley, T. P., Siow, R. C. M., Jacob, R., Mann, G. E. Reduced SERCA activity underlies dysregulation of Ca 2+ homeostasis under atmospheric O 2 levels. FASEB J. 32, 2531–2538 (2018). www.fasebj.org