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    TMCO1 Is an ER Ca(2+) Load-Activated Ca(2+) Channel.

    2016/8/26 Viewers:

    TMCO1 Is an ER Ca(2+) Load-Activated Ca(2+) Channel.

    Wang QC, et al.  Cell. 2016 Jun 2;165(6):1454-66.  PMID: 27212239 


    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 (generated by Shanghai Model Organisms Center, Inc) 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.


        * TMCO1 gene encodes an evolutionarily conserved ER transmembrane-spanning protein
        * Loss of TMCO1 causes overloading of ER Ca2+ store and mishandling of Ca2+ signaling
        * TMCO1 assembles into a Ca2+ selective channel in response to ER Ca2+ overloading
        * Ca2+ channel function of TMCO1 is disrupted by CFT dysplasia spectrum mutations