期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 286, 期 10, 页码 8577-8584出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M110.187179
关键词
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资金
- Austrian Science Foundation (FWF) [P22747, P211925, P21118]
- Hertha-Firnberg Scholarship [T442, T466]
- Austrian Academy of Sciences
- Austrian Science Fund (FWF) [P 21925, P 22747] Funding Source: researchfish
- Austrian Science Fund (FWF) [P21118, T442, T466, P22747] Funding Source: Austrian Science Fund (FWF)
Activation of immune cells is triggered by the Ca2+ release-activated Ca2+ current, which is mediated via channels of the Orai protein family. A key gating process of the three Orai channel isoforms to prevent Ca2+ overload is fast inactivation, most pronounced in Orai3. A subsequent reactivation is a unique gating characteristic of Orai1 channels, whereas Orai2 and Orai3 currents display a second, slow inactivation phase. Employing a chimeric approach by sequential swapping of respective intra- and extracellular regions between Orai1 and Orai3, we show here that Orai1 specific proline/arginine-rich domains in the N terminus mediate reactivation, whereas the second, intracellular loop modulates fast and slow gating processes. Swapping C-terminal strands lacks a significant impact. However, simultaneous transfer of Orai3 N terminus and its second loop or C terminus in an Orai1 chimera substantially increases fast inactivation centered between wild-type channels. Concomitant swap of all three cytosolic strands from Orai3 onto Orai1 fully conveys Orai3-like gating characteristics, in a strongly cooperative manner. In conclusion, Orai subtype-specific gating requires a cooperative interplay of all three cytosolic domains.
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