CO-AUTHORED BY VASLINA ZAYATS, SAURABH KUMAR PANDEY AND RUDIGER ETTRICH FROM CNSB- 1. A calcium accumulating region, CAR, in the Orai1 channel enhances Ca2+- permeation and SOCE-induced gene transcription. 2. Cholesterol binding modulates Orai1 channel function

In their first publication the authors focus on focus on how Orai1 enhances Ca2+ concentration at the pore. Store-operated calcium entry (SOCE) produces local calcium signals that not only refill intracellular calcium stores but also regulate specific downstream signaling events, such as activation of the calcium-dependent transcription factor NFAT. The channel complexes that mediate the calcium influx include the calcium-sensing proteins of the STIM family and the pore-forming subunits of the Orai family. These channels must function in cells that are part of tissues, as well as cells that circulate in the blood stream, thus cells that are exposed to very different concentrations of extracellular calcium. Using molecular dynamics simulations and analysis of mutant proteins in cells, Frischauf et al. identified a region, the calcium-accumulating region (CAR), in Orai1 that enhanced the local concentration of calcium at the entrance to the pore. The importance of CAR was most evident under conditions of low extracellular calcium, as would occur in cells of the skin. NFAT activity was impaired in cells expressing STIM1 and Orai channel proteins with mutations in CAR or that disrupted CAR function. Thus, CAR enables Orai to mediate SOCE-induced calcium signaling even under diverse extracellular calcium concentrations. Science Signaling one of the most prestigious scientific journals in the field published the paper online 22 Dec 2015.

Irene Frischauf*, Vasilina Zayats*, Michael Deix, Anna Hochreiter, Isaac Jardin Polo, Martin Muik, Barbara Lackner, Barbora Svobodova, Teresa Pammer, Monika Litvinukova, Amrutha Arumbakam Sridhar, Isabella Derler, Ivan Bogeski, Christoph Romanin, Rüdiger Ettrich**, Rainer Schindl** (2015) A calcium accumulating region, CAR, in the Orai1 channel enhances Ca2+- permeation and SOCE-induced gene transcription Science Signaling 8 (408): ra131. Dec 22.

In their second publication the authors focus on how Orai1 senses cholesterol Calcium in cells is stored in various compartments and released to initiate various cellular processes and signaling cascades. Orai proteins are the channel component of a complex that mediates the CRAC current, which mediates calcium influx into cells in response to the depletion of calcium from intracellular stores. Derler et al. found that cholesterol bound to Orai1, suppressing its activity and calcium influx. In mast cells, cholesterol depletion enhanced CRAC currents and degranulation, a process that releases inflammatory mediators such as histamine and requires increased intracellular calcium. Thus, cholesterol reduces the activity of Orai1 and calcium influx through this channel. Science Signalling published the paper online 26 Jan 2016.

Isabella Derler, Isaac Jardin, Peter B Stathopulos, Martin Muik, Marc Fahrner, Vaselina Zayats, Saurabh Pandey, Michael Poteser, Barbara Lackner, Marketa Absolonova, Klaus Groschner, Rüdiger Ettrich, Mitsu Ikura, Christoph Romanin (2016) Cholesterol binding modulates Orai1 channel function Science Signaling 9 (412): ra10. Jan 26.