Differential Redox Regulation of ORAI Ion Channels: A Mechanism to Tune Cellular Calcium Signaling

Bogeski, Ivan and Kummerow, Carsten and Al-Ansary, Dalia and Schwarz, Eva C and Koehler, R. and Kozai, D. and Takahashi, N. and Peinelt, Christine and Griesemer, D. and Bozem, Monika and Mori, Y. and Hoth, Markus and Niemeyer, Barbara A. (2010) Differential Redox Regulation of ORAI Ion Channels: A Mechanism to Tune Cellular Calcium Signaling. Science Signaling, 3 (115). ra24-ra24. ISSN 1937-9145

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Reactive oxygen species (ROS) are involved in many physiological and pathophysiological cellular processes.
We used lymphocytes, which are exposed to highly oxidizing environments during inflammation,
to study the influence of ROS on cellular function. Calcium ion (Ca2+) influx through Ca2+ release–activated
Ca2+ (CRAC) channels composed of proteins of the ORAI family is essential for the activation, proliferation,
and differentiation of T lymphocytes, but whether and how ROS affect ORAI channel function have
been unclear. Here, we combined Ca2+ imaging, patch-clamp recordings and measurements of cell proliferation
and cytokine secretion to determine the effects of hydrogen peroxide (H2O2) on ORAI channel
activity and human T helper lymphocyte (TH cell) function. ORAI1, but not ORAI3, channels were inhibited
by oxidation by H2O2. The differential redox sensitivity of ORAI1 and ORAI3 channels depended mainly
on an extracellularly located reactive cysteine, which is absent in ORAI3. TH cells became progressively
less redox-sensitive after differentiation into effector cells, a shift that would allow them to proliferate,
differentiate, and secrete cytokines in oxidizing environments. The decreased redox sensitivity of effector
TH cells correlated with increased expression of Orai3 and increased abundance of several cytosolic antioxidants.
Knockdown of ORAI3 with small-interfering RNA rendered effector TH cells more redox-sensitive.
The differential expression of Orai isoforms between naïve and effector TH cells may tune cellular responses
under oxidative stress.

Item Type: Article
Subjects: Medical and Health Sciences > Basic medicine
Medical and Health Sciences > Health sciences
Divisions: Faculty of Medical Science
Depositing User: Ivan Bogeski
Date Deposited: 27 Nov 2012 10:43
Last Modified: 07 Oct 2013 10:02
URI: https://eprints.ugd.edu.mk/id/eprint/2197

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