Critical parameters maintaining authentic CRAC channel hallmarks

Ca²⁺ ions represent versatile second messengers that regulate a huge diversity of processes throughout the cell's life. One prominent Ca²⁺ entry pathway into the cell is the Ca²⁺ release-activated Ca²⁺ (CRAC) ion channel. It is fully reconstituted by the two molecular key players: the stromal interaction molecule (STIM1) and Orai. STIM1 is a Ca²⁺ sensor located in the membrane of the endoplasmic reticulum, and Orai, a highly Ca²⁺ selective ion channel embedded in the plasma membrane. Ca²⁺ 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 Ca²⁺ selectivity with a reversal potential in the range of + 50 mV, small unitary conductance, fast Ca²⁺-dependent inactivation and enhancements in currents upon the switch from a Na⁺-containing divalent-free to a Ca²⁺-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.