Maintaining homeostasis of Ca²⁺ stores in the endoplasmic reticulum (ER) is crucial for proper Ca²⁺ signaling and key cellular functions. The Ca²⁺-release-activated Ca²⁺(CRAC) channel is responsible for Ca²⁺ influx and refilling after store depletion, but how cells cope with excess Ca²⁺ when ER stores are overloaded is unclear. We show that TMCO1 is an ER transmembrane protein that actively prevents Ca²⁺ stores from overfilling, acting as what we term a “Ca²⁺ load-activated Ca²⁺ channel” or “CLAC” channel. TMCO1 undergoes reversible homotetramerization in response to ER Ca²⁺overloading and disassembly upon Ca²⁺ depletion and forms a Ca²⁺-selective ion channel on giant liposomes. 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. Our findings indicate that TMCO1 provides a protective mechanism to prevent overfilling of ER stores with Ca²⁺ ions.

http://www.sciencedirect.com/science/article/pii/S0092867416304962