TMCO1 Is an ER Ca2+ Load-Activated Ca2+ Channel

Summary Maintaining homeostasis of Ca 2+ stores in the endoplasmic reticulum (ER) is crucial for proper Ca 2+ signaling and key cellular functions. The Ca 2+ -release-activated Ca 2+ (CRAC) channel is responsible for Ca 2+ influx and refilling after store depletion, but how cells cope with excess Ca 2+ when ER stores are overloaded is unclear. We show that TMCO1 is an ER transmembrane protein that actively prevents Ca 2+ stores from overfilling, acting as what we term a "Ca 2+ load-activated Ca 2+ channel" or "CLAC" channel. TMCO1 undergoes reversible homotetramerization in response to ER Ca 2+ overloading and disassembly upon Ca 2+ depletion and forms a Ca 2+ -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 Ca 2+ in cells. Our findings indicate that TMCO1 provides a protective mechanism to prevent overfilling of ER stores with Ca 2+ ions.