Differential redox regulation of ORAI ion channels: a mechanism to tune cellular calcium signaling.

Bogeski, Ivan; Kummerow, Carsten; Al-Ansary, Dalia; Schwarz, Eva C; Koehler, Richard; Kozai, Daisuke; Takahashi, Nobuaki; Peinelt, Christine; Griesemer, Desiree; Bozem, Monika; Mori, Yasuo; Hoth, Markus; Niemeyer, Barbara A (2010). Differential redox regulation of ORAI ion channels: a mechanism to tune cellular calcium signaling. Science signaling, 3(115), ra24. American Association for the Advancement of Science 10.1126/scisignal.2000672

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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 (Ca(2+)) influx through Ca(2+) release-activated Ca(2+) (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 Ca(2+) imaging, patch-clamp recordings, and measurements of cell proliferation and cytokine secretion to determine the effects of hydrogen peroxide (H(2)O(2)) on ORAI channel activity and human T helper lymphocyte (T(H) cell) function. ORAI1, but not ORAI3, channels were inhibited by oxidation by H(2)O(2). The differential redox sensitivity of ORAI1 and ORAI3 channels depended mainly on an extracellularly located reactive cysteine, which is absent in ORAI3. T(H) 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 T(H) cells correlated with increased expression of Orai3 and increased abundance of several cytosolic antioxidants. Knockdown of ORAI3 with small-interfering RNA rendered effector T(H) cells more redox-sensitive. The differential expression of Orai isoforms between naïve and effector T(H) cells may tune cellular responses under oxidative stress.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Pre-clinic Human Medicine > Institute of Biochemistry and Molecular Medicine

UniBE Contributor:

Peinelt, Christine

Subjects:

500 Science > 570 Life sciences; biology
600 Technology > 610 Medicine & health

ISSN:

1937-9145

Publisher:

American Association for the Advancement of Science

Language:

English

Submitter:

Christine Peinelt

Date Deposited:

14 Jun 2018 10:06

Last Modified:

25 Oct 2019 03:35

Publisher DOI:

10.1126/scisignal.2000672

PubMed ID:

20354224

BORIS DOI:

10.7892/boris.97460

URI:

https://boris.unibe.ch/id/eprint/97460

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