The anatomy of native CRAC channel(s)

The ubiquitous store-operated Ca²⁺ entry pathway mediated by plasma membrane Ca²⁺ release-activated Ca²⁺ (CRAC) channels regulates a wide variety of physiological functions. While it is clearly established that the ORAI1 protein is essential for native mammalian CRAC channels, the contribution of ORAI2 and ORAI3 have remained nebulous. The crystal structure of the sole Orai isoform in drosophila (dOrai) revealed a hexameric assembly, suggesting that mammalian CRAC channels are hexamers of ORAI. Nevertheless, the relative contribution of each isoform of the mammalian ORAI trio to the stoichiometry of native CRAC channels remains elusive. The recent generation of ORAI isoform single, double and triple knockout cell lines and tissue-specific knockout mice has shed light on how native ORAI isoform heteromerization fine tunes CRAC-mediated Ca²⁺ signaling.