The Transmembrane and coiled-coil domains protein 1 (TMCO1, TMCC4, PNAS-10, PNAS-136, UNQ155) of 188 aas and 3 TMSs. It is an ER transmembrane protein that actively prevents Ca²⁺ stores from overfilling, acting as a "Cacium Load-activated Calcium channel" or "CLAC" channel. TMCO1 undergoes reversible homotetramerization in response to ER Ca²⁺ overloading and disassembly upon Ca²⁺ depletion to form a Ca²⁺-selective ion channel as demonstrated in liposomes (Wang et al. 2016). TMCO1 knockout mice reproduce the main clinical features of human cerebrofaciothoracic (CFT) dysplasia spectrum, a developmental disorder linked to TMCO1 dysfunction, and exhibit severe mishandling of ER Ca²⁺ in cells (Alanay et al. 2014). Thus, TMCO1 provides a protective mechanism to prevent overfilling of ER stores with calcium ions (Wang et al. 2016). It regulates Ca²⁺ stores in granulosa cells (Sun et al. 2018).  TMCO1-mediated Ca²⁺ leak underlies osteoblast functions via CaMKII signaling (Li et al. 2019). The TMCO1 gene is a tumor suppressor in urinary bladder urothelial carcinomas (UBUC). TMCO1 dysregulates cell-cycle progression via suppression of the AKT pathway, and S60 of the TMCO1 protein is crucial for its tumor-suppressor roles (Li et al. 2017). Batchelor-Regan et al. 2021 published a short review about the clinical and scientific advances made with TMCO1. Ca²⁺ homeostasis maintained by TMCO1 underlies corpus callosum development via ERK signaling (Yang et al. 2022). A mechanism of metformin action, restoring cellular ER homeostasis, enabled the development of a nanocarrier-mediated ER targeting strategy for remodeling diabetic periodontal tissue (Zhong et al. 2022).