The Evolving Picture of Ca2+ Leak from Endoplasmic Reticulum in Health and Diseases

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Background

The endoplasmic reticulum (ER) is one of the two main reservoirs for releasable Ca2+ in the cell and usually maintains free Ca2+ concentrations at least three orders of magnitude higher than in the cytosol. Therefore, it is remarkable that the ER membrane is not tight to ions; it has indeed a distinct permeability to ions and even small molecules. When the sarcoplasmic/endoplasmic reticulum Ca2+ ATP-ases (SERCA), which pumps Ca2+ into the ER, is blocked, the Ca2+ concentration in the ER decreases spontaneously, unmasking the Ca2+ leakage or passive Ca2+ efflux from the ER. Within several molecular pathways for Ca2+ leakage that co-exist in ER membranes, Sec61 translocons are unparalleled because they support both translocation of proteins into the ER and Ca2+ leakage from the ER, suggesting a dynamic coupling between ER membrane permeability and protein synthesis. Furthermore, these translocons are ubiquitous and highly abundant. Therefore, it is not surprising that the Sec61-mediated Ca2+ leakage from the ER has been implicated in the etiology of various cancers, neurodegeneration, and immunodeficiency as well. A picture is evolving in which the Sec61-mediated Ca2+ leakage from the ER provides a link between energetic requirements of, protein translocation into and processing within the ER.

In general, the Ca2+ leakage from the endoplasmic reticulum (ER) and specifically, the Sec61-mediated Ca2+ leakage from the ER represent a new and unexpected mechanisms of the ER Ca2+ homeostasis. Goal of the Research Topic is to present state-of-the-art studies that cover aspects of the Ca2+ leak from ER in health and diseases. We would like to address questions on how the Ca2+ leakage from ER is integrated into ER Ca2+ homeostasis and, eventually, in the energy supply to the ER. Considering that Sec61 translocons function as ion channels in the ER membrane, it will be interesting to explore the pore structure and eventually the open-closed kinetics of these unusual ion channels. It is remarkable that the Sec61-mediated Ca2+ leak from the ER has been implicated in the etiology of diseases such as cancer and immunodeficiency. A good proportion of the papers in the Research Topic will therefore focus on ER Ca2+ leakage in diseases. Finally, a number of small molecules that inhibit protein translocation have been described and we would like to present papers looking for their mode of action with focus on the ER Ca2+ leak.

We would like to present the state-of-the-art studies on Ca2+ leakage from the endoplasmic reticulum (ER) in health and diseases and, accordingly, the themes that fit best within the scope are:

1) Structure of the Sec61 translocon as one of the main ion leak channels in the ER.
2) Ca2+ leakage from the ER with focus on Sec61 translocons and their role in ER Ca2+ homeostasis and energy supply to the ER.
3) General mechanism involved in the ER Ca2+ homeostasis such as Ca2+ binding chaperones and, eventually, SERCA pumps.
4) Channelopathies related to ER Ca2+ leak in prostate and other cancers, neurodegeneration, and immunodeficiency.
5) Pharmacology of the ER Ca2+ leak including small molecules such as eeyarestatin, mycolactone, Ipomoeassin F, coibamide A and apratoxin A, which are potential modulators of the Sec61-mediated Ca2+ leak.
6) Imaging Ca2+ in the ER.

Keywords: Calcium leak, Calcium homeostasis, endoplasmic reticulum, translocon, Sec61 complex

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