A calcium-accumulating region, CAR, in the channel Orai1 enhances Ca(2+) permeation and SOCE-induced gene transcription

The Ca(2+) release-activated Ca(2+) channel mediates Ca(2+) influx in a plethora of cell types, thereby controlling diverse cellular functions. The channel complex is composed of stromal interaction molecule 1 (STIM1), an endoplasmic reticulum Ca(2+)-sensing protein, and Orai1, a plasma membrane Ca(...

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Bibliographic Details
Published in:	Science signaling Vol. 8; no. 408; p. ra131
Main Authors:	Frischauf, Irene, Zayats, Vasilina, Deix, Michael, Hochreiter, Anna, Jardin, Isaac, Muik, Martin, Lackner, Barbara, Svobodová, Barbora, Pammer, Teresa, Litviňuková, Monika, Sridhar, Amrutha Arumbakam, Derler, Isabella, Bogeski, Ivan, Romanin, Christoph, Ettrich, Rüdiger H, Schindl, Rainer
Format:	Journal Article
Language:	English
Published:	United States 22-12-2015
Subjects:	Animals Calcium - metabolism Cell Membrane Permeability - physiology Drosophila melanogaster Drosophila Proteins - chemistry Drosophila Proteins - genetics Drosophila Proteins - metabolism HEK293 Cells Humans Ion Transport - physiology Membrane Proteins - chemistry Membrane Proteins - genetics Membrane Proteins - metabolism ORAI1 Protein Protein Structure, Secondary Stromal Interaction Molecule 1 Transcription, Genetic - physiology
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Summary:	The Ca(2+) release-activated Ca(2+) channel mediates Ca(2+) influx in a plethora of cell types, thereby controlling diverse cellular functions. The channel complex is composed of stromal interaction molecule 1 (STIM1), an endoplasmic reticulum Ca(2+)-sensing protein, and Orai1, a plasma membrane Ca(2+) channel. Channels composed of STIM1 and Orai1 mediate Ca(2+) influx even at low extracellular Ca(2+) concentrations. We investigated whether the activity of Orai1 adapted to different environmental Ca(2+) concentrations. We used homology modeling and molecular dynamics simulations to predict the presence of an extracellular Ca(2+)-accumulating region (CAR) at the pore entrance of Orai1. Furthermore, simulations of Orai1 proteins with mutations in CAR, along with live-cell experiments, or simulations and electrophysiological recordings of the channel with transient, electrostatic loop3 interacting with loop1 (the site of CAR) determined that CAR enhanced Ca(2+) permeation most efficiently at low external Ca(2+) concentrations. Consistent with these results, cells expressing Orai1 CAR mutants exhibited impaired gene expression stimulated by the Ca(2+)-activated transcription factor nuclear factor of activated T cells (NFAT). We propose that the Orai1 channel architecture with a close proximity of CAR to the selectivity filter, which enables Ca(2+)-selective ion permeation, enhances the local extracellular Ca(2+) concentration to maintain Ca(2+)-dependent gene regulation even in environments with relatively low Ca(2+)concentrations.
ISSN:	1937-9145
DOI:	10.1126/scisignal.aab1901