TMCO1 functions as an ER Ca~(2+) load-activated Ca~(2+)(CLAC) release channel
【摘要】：Endoplasmic reticulum(ER) Ca~(2+) store homeostasis is crucial for the proper Ca~(2+) signaling and cellular functions. It has been established that Ca~(2+)-release-activated Ca~(2+)(CRAC) channel is responsible for the Ca~(2+) influx and Ca~(2+) store refilling after store depletion. However, it is unclear whether the ER Ca~(2+) store can expel the excess Ca~(2+) when the store gets overloaded. Here we show that TMCO1 is an ER transmembrane protein that actively prevents Ca~(2+) store from overfilling. TMCO1 undergoes reversible homo-tetramerization/disassembly in response to ER Ca~(2+) overloading/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 and exhibit a severe mishandling of ER Ca~(2+) in cells. These findings reveal TMCO1 to be a novel Ca~(2+) channel for ER Ca~(2+) homeostatic maintenance. We name this Ca~(2+) load-activated Ca~(2+) channel "CLAC" channel, a function disrupted by human CFT dysplasia spectrum mutations.