Critical parameters maintaining authentic CRAC channel hallmarks

Ca(2+) ions represent versatile second messengers that regulate a huge diversity of processes throughout the cell’s life. One prominent Ca(2+) entry pathway into the cell is the Ca(2+) release-activated Ca(2+) (CRAC) ion channel. It is fully reconstituted by the two molecular key players: the stromal interaction molecule (STIM1) and Orai. STIM1 is a Ca(2+) sensor located in the membrane of the endoplasmic reticulum, and Orai, a highly Ca(2+) selective ion channel embedded in the plasma membrane. Ca(2+) store-depletion leads initially to the activation of STIM1 which subsequently activates Orai channels via direct binding. Authentic CRAC channel hallmarks and biophysical characteristics include high Ca(2+) selectivity with a reversal potential in the range of + 50 mV, small unitary conductance, fast Ca(2+)-dependent inactivation and enhancements in currents upon the switch from a Na(+)-containing divalent-free to a Ca(2+)-containing solution. This review provides an overview on the critical determinants and structures within the STIM1 and Orai proteins that establish these prominent CRAC channel characteristics. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s00249-019-01355-6) contains supplementary material, which is available to authorized users.