The CRAC channel protein, Orai1 (CRACM1) (Prakriya et al. 2006), complexed with the STIM1 or STIM2 protein (Feske et al., 2006). Replacement of the conserved glutamate in the first TMS  with glutamine (E106Q) acts as a dominant-negative protein, and substitution with aspartate (E106D) enhances Na⁺, Ba²⁺, and Sr²⁺ permeation relative to Ca²⁺. Mutating E190Q in TMS3 also affects channel selectivity, suggesting that glutamate residues in both TMS1 and TMS3 face the lumen of the pore (Vig et al. 2006). The Orai1:Stim stoichiometry = 4:2 (Ji et al., 2008). Human Orai1 and Orai3 channels are dimeric in the closed resting state and open states. They are tetrameric when complexed with STIM1 (Demuro et al., 2011). A dimeric form catalyzes nonselective cation conductance in the STIM1-independent mode.  STIM1 domains have been characterized (How et al. 2013). Alternative translation initiation of the Orai1 message produces long and short types of Ca²⁺ channels with distinct signaling and regulatory properties (Desai et al. 2015).  STIM2 plays roles similar to STIM1 in regulating basal cytosolic and endoplasmic reticulum Ca²⁺ concentrations by controling Orai1, 2 and 3.  STIM2 may inhibit STIM1-mediated Ca²⁺ influx.  It also regulates protein kinase A-dependent phosphorylation and trafficking of AMPA receptors (TC# 1.A.10) (Garcia-Alvarez et al. 2015). A mechanistic model for ROS (H₂O₂)-mediated inhibition of Orai1 has been determined (Alansary et al. 2016). Regions that are important for the optimal assembly of hetero-oligomers composed of full-length STIM1 with its minimal STIM1-ORAI activating region, SOAR, have been identified (Ma et al. 2017). Orai1 may be multifunctional (Carrell et al. 2016). Activatioin of Orai1 requires communication between the N-terminus and loop 2 (Fahrner et al. 2017). STIM1 dimers unfold to expose a discrete STIM-Orai activating region (SOAR1) that tethers and activates Orai1 channels within discrete ER-PM junctions (Zhou et al. 2018). SOAR dimer cross-linking leads to substantial Orai1 channel clustering, resulting in increased efficacy and cooperativity of Orai1 channel function. In addition to being an ER Ca²⁺ sensor, STIM1 functions within the PM to exert control over the operation of SOCs. As a cell surface signaling protein, STIM1 represents a key pharmacological target to control fundamental Ca²⁺-regulated processes including secretion, contraction, metabolism, cell division, and apoptosis (Spassova et al. 2006). STIM1 also contributes to smooth muscle contractility (Feldman et al. 2017). STIM1-mediated Orai1 channel gating, involves bridges between TMS 1 and the surrounding TMSs 2/3 ring, and these are critical for conveying the gating signal to the pore (Yeung et al. 2018). A review article summarizes the current high resolution structural data on specific EF-hand, sterile alpha motif and coiled-coil interactions which drive STIM function in the activation of Orai1 channels (Novello et al. 2018). Orai1 and STIM1 are involved in tubular aggregate myopathy (Wu et al. 2018). Knowledge of the structure-function relationships of CRAC channels, with a focus on key structural elements that mediate the STIM1 conformational switch and the dynamic coupling between STIM1 and ORAI1 has been discussed (Nguyen et al. 2018). While STIM1 is the native channel opener, a chemical modulator is 2-aminoethoxydiphenyl borate (2-APB) (Ali et al. 2017). ORAI1 channel gating and selectivity iare differentially altered by natural mutations in the first and third transmembrane domains (Bulla et al. 2018). Stim1 responds to both ER Ca²⁺ depletion and heat, mediates temperature-induced Ca²⁺ influx in skin keratinocytes via coupling to Orai Ca²⁺ channels in the plasma membrane, and thereby brings about thermosensing (Liu et al. 2019). Possibly, the interplay between STIM1 alpha3 and Orai1 TM3 allows STIM1 coupling to be transmitted into physiological CRAC channel activation (Butorac et al. 2019). Blockage of store-operated Ca²⁺ influx by synta66 is mediated by direct inhibition of the Ca²⁺ selective orai1 pore (Waldherr et al. 2020). The carboxy terminal coiled-coil region modulates Orai1 internalization during meiosis (Hodeify et al. 2021). ORAI1 mutations disrupt channel trafficking, resulting in combined immunodeficiency (Yu et al. 2021). Orai channel C-terminal peptides are key modulators of STIM-Orai coupling and calcium signal generation (Baraniak et al. 2021). Conformational surveillance of Orai1 by a rhomboid intramembrane protease prevents inappropriate CRAC channel activation (Grieve et al. 2021). STIM1-dependent peripheral coupling governs the contractility of vascular smooth muscle cells (Krishnan et al. 2022). Gating checkpoints in the Orai1 calcium channel have been identified (Augustynek et al. 2022).  Photocrosslinking-induced CRAC channel-like Orai1 activation occurs independently of STIM1 (Maltan et al. 2023). The Ca²⁺ channel ORAI1 is a regulator of oral cancer growth and nociceptive pain (Son et al. 2023).  In T cells, STIM and Orai are dispensable for conventional T cell development, but critical for activation and differentiation. Gross et al. 2023 reviewed novel STIM-dependent mechanisms for control of Ca²⁺ signals during T cell activation and its impact on mitochondrial function and transcriptional activation for control of T cell differentiation and function.