Insights into the dynamics of the Ca²⁺ release-activated Ca²⁺ channel pore-forming complex Orai1 Available to Purchase

An important calcium (Ca²⁺) entry pathway into the cell is the Ca²⁺ release-activated Ca²⁺ (CRAC) channel, which controls a series of downstream signaling events such as gene transcription, secretion and proliferation. It is composed of a Ca²⁺ sensor in the endoplasmic reticulum (ER), the stromal interaction molecule (STIM), and the Ca²⁺ ion channel Orai in the plasma membrane (PM). Their activation is initiated by receptor-ligand binding at the PM, which triggers a signaling cascade within the cell that ultimately causes store depletion. The decrease in ER-luminal Ca²⁺ is sensed by STIM1, which undergoes structural rearrangements that lead to coupling with Orai1 and its activation. In this review, we highlight the current understanding of the Orai1 pore opening mechanism. In this context, we also point out the questions that remain unanswered and how these can be addressed by the currently emerging genetic code expansion (GCE) technology. GCE enables the incorporation of non-canonical amino acids with novel properties, such as light-sensitivity, and has the potential to provide novel insights into the structure/function relationship of CRAC channels at a single amino acid level in the living cell.