Calcium ion (Ca²⁺) is a highly versatile intracellular signal that controls many different cellular functions such as contraction, secretion, memory formation, gene transcription, cell growth and cell death. Endoplasmic reticulum (ER) is the main intracellular Ca²⁺ store, and maintaining homeostasis of Ca²⁺ stores in the ER is crucial for proper Ca²⁺ signaling and key cellular functions. Disarrangement of ER Ca²⁺ homeostasis has been implicated in many severe diseases. It is known that 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.

In collaboration with Dr. Aimin Zhou in the Department of Chemistry and GRHD at Cleveland State University, Dr. Quan Chen in the Institute of Zoology at Chinese Academy of Sciences, Dr. Yang Li in the Shanghai Institute of Materia Medica at Chinese Academy of Sciences, Dr. Tie-Shan Tang’s team identifies TMCO1 as an ER Ca²⁺ channel which detects ER Ca²⁺ overfilling and actively regulates ER Ca²⁺ content. TMCO1 is capable of sensing the ER Ca²⁺ overload status, assembling into a Ca²⁺ channel by homo-tetramerization and thus releasing Ca²⁺ from ER store. Intriguingly, TMCO1 tetramers rapidly disassemble to terminate the Ca²⁺ channel activity when ER Ca²⁺ returns to resting levels. They name this channel as Ca²⁺ load-activated Ca²⁺ (CLAC) release channel. The CLAC channel may constitute a conserved mechanism for cell to prevent ER Ca²⁺ store from overfilling and thus maintain a homeostasis in ER Ca²⁺ store. TMCO1-defect syndrome mutations result in the CLAC channel disruption, which could be the underlying pathogenic mechanisms for human CFT dysplasia spectrum. Therefore, CLAC functions as a conserved, important regulator of ER Ca²⁺ homeostasis and thus provides a protective mechanism to prevent overfilling of ER stores with Ca²⁺ ions.

This work was published in Cell ahead of print on May 19, 2016, doi: 10.1016/j.cell.2016.04.051

Paper link：http://dx.doi.org/10.1016/j.cell.2016.04.051

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