Intracellular Ca2+ storage in health and disease: A dynamic equilibrium
ABSTRACT Homeostatic control of the endoplasmic reticulum (ER) both as the site for protein handling (synthesis, folding, trafficking, disaggregation and degradation) and as a Ca2+ store is of crucial importance for correct functioning of the cell. Disturbance of the homeostatic control mechanisms leads to a vast array of severe pathologies. The Ca2+ content of the ER is a dynamic equilibrium between active uptake via Ca2+ pumps and Ca2+ release by a number of highly regulated Ca2+-release channels. Regulation of the Ca2+-release channels is very complex and several mechanisms are still poorly understood or controversial. There is increasing evidence that a number of unrelated proteins, either by themselves or in association with other Ca2+ channels, can provide additional Ca2+-leak pathways. The ER is a dynamic organelle and changes in its size and components have been described, either as a result of (de)differentiation processes affecting the secretory capacity of cells, or as a result of adaptation mechanisms to diverse stress conditions such as the unfolded protein response and autophagy. In this review we want to give an overview of the current knowledge of the (short-term) regulatory mechanisms that affect Ca2+-release and Ca2+-leak pathways and of the (long-term) adaptations in ER size and capacity. Understanding of the consequences of these mechanisms for cellular Ca2+ signaling could provide a huge therapeutic potential.
SourceAvailable from: Bengt Westermark[Show abstract] [Hide abstract]
ABSTRACT: Tumor-initiating cells are a subpopulation in aggressive cancers that exhibit traits shared with stem cells, including the ability to self-renew and differentiate, commonly referred to as stemness. In addition, such cells are resistant to chemo- and radiation therapy posing a therapeutic challenge. To uncover stemness-associated functions in glioma-initiating cells (GICs), transcriptome profiles were compared to neural stem cells (NSCs) and gene ontology analysis identified an enrichment of Ca2+ signaling genes in NSCs and the more stem-like (NSC-proximal) GICs. Functional analysis in a set of different GIC lines regarding sensitivity to disturbed homeostasis using A23187 and Thapsigargin, revealed that NSC-proximal GICs were more sensitive, corroborating the transcriptome data. Furthermore, Ca2+ drug sensitivity was reduced in GICs after differentiation, with most potent effect in the NSC-proximal GIC, supporting a stemness-associated Ca2+ sensitivity. NSCs and the NSC-proximal GIC line expressed a larger number of ion channels permeable to potassium, sodium and Ca2+. Conversely, a higher number of and higher expression levels of Ca2+ binding genes that may buffer Ca2+, were expressed in NSC-distal GICs. In particular, expression of the AMPA glutamate receptor subunit GRIA1, was found to associate with Ca2+ sensitive NSC-proximal GICs, and decreased as GICs differentiated along with reduced Ca2+ drug sensitivity. The correlation between high expression of Ca2+ channels (such as GRIA1) and sensitivity to Ca2+ drugs was confirmed in an additional nine novel GIC lines. Calcium drug sensitivity also correlated with expression of the NSC markers nestin (NES) and FABP7 (BLBP, brain lipid-binding protein) in this extended analysis. In summary, NSC-associated NES+/FABP7+/GRIA1+ GICs were selectively sensitive to disturbances in Ca2+ homeostasis, providing a potential target mechanism for eradication of an immature population of malignant cells.PLoS ONE 12/2014; 9(12):e115698. DOI:10.1371/journal.pone.0115698 · 3.53 Impact Factor
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ABSTRACT: Even though endoplasmic reticulum (ER) stress associated with mycobacterial infection has been well studied, the molecular basis of ER as a crucial organelle to determine the fate of Mtb is yet to be established. Here, we have studied the ability of Mtb to manipulate the ultrastructural architecture of macrophage ER and found that the ER-phenotypes associated with virulent (H37Rv) and avirulent (H37Ra) strains were different: a rough ER (RER) with the former against a smooth ER (SER) with the later. Further, the functional attributes of these changes were probed by MS-based quantitative proteomics (133 ER proteins) and lipidomics (8 phospholipids). Our omics approaches not only revealed the host pathogen cross-talk but also emphasized how precisely Mtb uses proteins and lipids in combination to give rise to characteristic ER-phenotypes. H37Ra-infected macrophages increased the cytosolic Ca2+ levels by attenuating the ATP2A2 protein and simultaneous induction of PC/PE expression to facilitate apoptosis. However, H37Rv inhibited apoptosis and further controlled the expression of EST-1 and AMRP proteins to disturb cholesterol homeostasis resulting in sustained infection. This approach offers the potential to decipher the specific roles of ER in understanding the cell biology of mycobacterial infection with special reference to the impact of host response.02/2015; 2015:1-13. DOI:10.1155/2015/270438
01/2015; Springer International Publishing., ISBN: 9783319122526