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Sci. Signal., 30 March 2010
Vol. 3, Issue 115, p. ra24
[DOI: 10.1126/scisignal.2000672]


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

Ivan Bogeski1*, Carsten Kummerow1{dagger}, Dalia Al-Ansary1{dagger}, Eva C. Schwarz1, Richard Koehler1, Daisuke Kozai2, Nobuaki Takahashi2, Christine Peinelt1, Desiree Griesemer1{ddagger}, Monika Bozem1, Yasuo Mori2, Markus Hoth1, and Barbara A. Niemeyer1*

1 Department of Biophysics, Saarland University, 66421 Homburg, Germany.
2 Department of Synthetic Chemistry and Biological Chemistry, Kyoto University, Kyoto 615-8510, Japan.

{dagger} These authors contributed equally to this work.

{ddagger} Present address: Department of Biology, Technische Universität Kaiserslautern, 67663 Kaiserslautern, Germany.

Abstract: 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.

* To whom correspondence should be addressed. E-mail: ivan.bogeski{at} (I.B.); barbara.niemeyer{at} (B.A.N.)

Citation: I. Bogeski, C. Kummerow, D. Al-Ansary, E. C. Schwarz, R. Koehler, D. Kozai, N. Takahashi, C. Peinelt, D. Griesemer, M. Bozem, Y. Mori, M. Hoth, B. A. Niemeyer, Differential Redox Regulation of ORAI Ion Channels: A Mechanism to Tune Cellular Calcium Signaling. Sci. Signal. 3, ra24 (2010).

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