ORAI1 functions as the pore-forming subunit of calcium release-activated calcium (CRAC) channels, which mediate store-operated calcium entry (SOCE) in non-excitable cells 1. When endoplasmic reticulum calcium stores are depleted, STIM1 senses the reduced calcium levels and activates ORAI1 channels in the plasma membrane, allowing sustained calcium influx essential for cellular functions and store refilling 2. The mechanism involves STIM1 binding to ORAI1, forming a highly calcium-selective ion channel complex that triggers calcium-dependent processes including gene transcription, T-cell activation, and mast cell degranulation 2. Disease relevance includes CRAC channelopathies caused by ORAI1 mutations, which result in abolished CRAC channel currents, lack of SOCE, and clinically manifest as immunodeficiency, congenital myopathy, and anhydrotic ectodermal dysplasia 13. ORAI1 is also implicated in breast cancer progression through regulation of gene expression, including PTGS2 and IL6, dependent on its pore function and STIM1 binding 4. Additionally, aging-related microvascular dysfunction involves increased ORAI1 expression, contributing to vascular hypercontractility 5.