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SHR Neuro Cancer Cardio Lipid Metab Microb
Frischauf, I; Schindl, R; Bergsmann, J; Derler, I; Fahrner, M; Muik, M; Fritsch, R; Lackner, B; Groschner, K; Romanin, C.
Cooperativeness of Orai cytosolic domains tunes subtype-specific gating.
J Biol Chem. 2011; 286(10):8577-8584
Doi: 10.1074/jbc.M110.187179
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- Leading authors Med Uni Graz
- Schindl Rainer
- Co-authors Med Uni Graz
- Groschner Klaus
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- Abstract:
- Activation of immune cells is triggered by the Ca(2+) release-activated Ca(2+) current, which is mediated via channels of the Orai protein family. A key gating process of the three Orai channel isoforms to prevent Ca(2+) 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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