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

Cell. 2016 Jun 2;165(6):1454-1466. doi: 10.1016/j.cell.2016.04.051. Epub 2016 May 19.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Ataxia / genetics
  • COS Cells
  • Calcium / metabolism
  • Calcium Channels / genetics
  • Calcium Channels / metabolism*
  • Chlorocebus aethiops
  • Endoplasmic Reticulum / metabolism*
  • HEK293 Cells
  • HeLa Cells
  • Humans
  • Intellectual Disability / genetics
  • Intracellular Membranes / metabolism
  • Mice
  • Mice, Knockout
  • Osteogenesis / genetics
  • Sequence Alignment


  • Calcium Channels
  • TMCO1 protein, mouse
  • Calcium