Editorial: The evolving picture of Ca2+ leak from endoplasmic reticulum in health and diseases

Abstract

Editorial on the Research Topic The evolving picture of Ca²⁺leak from endoplasmic reticulum in health and diseases The endoplasmic reticulum (ER) is one of the two main reservoirs for releasable Ca²⁺ in the cell and usually maintains free Ca²⁺ concentrations of 100–800 μM, which amounts to at least three orders of magnitude higher than in the cytosol (Berridge et al., 2000; Berridge, 2002) (Figure 1A). 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 pump Ca²⁺ into the ER, is blocked, e.g., by thapsigargin, the Ca²⁺ concentration in the ER decreases, unmasking the Ca²⁺ leak/leakage or passive Ca²⁺ efflux from the ER. In the absence of extracellular Ca²⁺, the SERCA inhibition typically leads to a decrease in ER Ca²⁺ with the corresponding transient increase of cytosolic Ca²⁺ (Gamayun et al., 2019). 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 (Figure 1B). 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 infectious diseases (such as Buruli ulcer) as well as inherited diseases, such as immunodeficiency, neutropenia and tubulointerstitial kidney disease (Bolar et al., 2016; Schubert et al., 2018; Van Nieuwenhove et al., 2020; Bhadra et al., 2021; Sicking et al., 2022). Notably, the other ER membrane resident Ca²⁺ leak channels are, in alphabetical order, Bcl-2 (Pinton et al., 2001; Chami et al., 2004), CALHM1 (Gallego-Sandín et al., 2011), Pannexin 1 (Abeele et al., 2006), Presenillins 1 and 2 (Tu et al., 2006), truncated SERCA variants (Chami et al., 2001; Chami et al., 2008) and transient receptor potential superfamily members TRPC1 (Berbey et al., 2009) and TRPP2 (see below). In contrast to the latter proteins, however, the Sec61 translocons are ubiquitous and highly abundant, depending on secretory capacity of the cell, i.e., the extension of the ER (Pick et al., 2021). In HeLa cells, for example, the concentration of heterotrimeric Sec61 complexes is between 139 and 456 nM (judging from the concentration of the subunit with the lowest and highest cellular concentration, respectively, (Lang et al., 2017), and Sec61 channels support about 60% of the Ca²⁺ leakage from the ER (Lang et al., 2011; Gamayun et al., 2019). FIGURE 1. I The endoplasmic reticulum (ER) of nucleated human cells has major functions in cellular calcium homeostasis and contains the abundant and ubiquitous Sec61 channel. (A) The ER is shown here in a HEK293 cell after fluorescence microscopy after staining with ER-Tracker™ Red (BODIPY™ TR Glibenclamide), the plasma membrane was stained with CellMask™ Green Plasma Membrane Stain (details are given by Pick et al.). The image was kindly provided by Tillman Pick (Experimental and Clinical Pharmacology and Toxicology, Saarland University). (B) The Sec61 channel is shown in its modeled closed (top) and open (bottom) conformational states, as indicated (adopted from Lang et al., 2017). These two states are proposed to be in a dynamic equilibrium with each other. The fully open state of the Sec61 channel allows the initial entry of precursor polypeptides from the cytosol into the ER lumen and ER membrane, respectively. In addition, it allows the passive efflux of Ca²⁺ from the ER lumen into the cytosol after termination of the translocation process and, therefore, it can be quantified in live cell Ca²⁺ imaging in cytosol and ER lumen using ratiometric dyes and fluorescent proteins. Ca²⁺ efflux may also be possible in the transition state (not shown), which can be detected in the presence of Sec61 channel inhibitors such as Eeyarestatins or Mycolactone and may be identical to the so-called primed state that can be induced by ribosomes in co-translational- and by the Sec62/Sec63 complex in post-translational-transport (Gamayun et al., 2019; Bhadra et al., 2021). Originally, the Ca²⁺ leakage from the ER and specifically, the Sec61-mediated Ca²⁺ leakage from the ER represented a new and unexpected mechanisms of the ER Ca²⁺ homeostasis. It first came up in the early 2,000 years in seminal papers on human cells (Camello et al., 2002; Lomax et al., 2002; Van Coppenolle et al., 2004; Flourakis et al., 2006; Giunti et al., 2007) and, subsequently, was confirmed in vivo by a global RNAi screen for genes that are involved in store-operated Ca²⁺ entry (SOCE) in Drosophila (Zhang et al., 2006) as well as by biochemical and biophysical approaches (Wirth et al., 2003; Erdmann et al., 2011; Lang et al., 2011; Schäuble et al., 2012). The latter experimental approaches involved single channel recordings from purified and reconstituted Sec61 complexes and live cell calcium imaging in cytosol and ER lumen of human cells in combination with siRNA treatment or plasmid driven mutant variant expression. Several studies also identified various interaction partners of the Sec61 channel that are involved in tight control of the Ca²⁺ leak (Figure 1B), i.e., the ER-lumenal chaperone BiP and its cochaperones ERj3 and ERj6 (Schäuble et al., 2012; Schorr et al., 2015) as well as cytosolic calmodulin (CaM) and the ER membrane protein Sec62 (Erdmann et al., 2011; Linxweiler et al., 2013), thereby preventing excessive Ca²⁺ leakage that may lead to apoptosis...