Impairment of Store-operated Calcium Entry: Implications in Alzheimer’s Neurodegeneration

2021 ◽  
Vol 17 (12) ◽  
pp. 1088-1094
Author(s):  
Jing Zhou ◽  
Shengzhou Wu
Keyword(s):  
Endoplasmic Reticulum ◽  
Neurodegenerative Disorder ◽  
Therapeutic Potential ◽  
Alternative Hypothesis ◽  
Cholinergic Neurons ◽  
Proteasome Inhibition ◽  
Calcium Entry ◽  
Calcium Sensors ◽  
Store Operated Calcium Entry ◽  
Er Calcium

Alzheimer's disease (AD) is an insidious and progressive neurodegenerative disorder. Dysfunction of central cholinergic neurons, amyloid aggregation and deposition,oxidative stress,and biometal dyshomeostasis has been regarded as the major pathogenic mediators in this devastating disease. However, strategies derived from these hypotheses fail to slow down or stop the progression of AD, warranting a combination of therapies to target multiple etiological factors or examining alternative hypothesis. Store-operated calcium entry (SOCE) is the process by which depletion of calcium in the endoplasmic reticulum (ER) lumen causes an influx of calcium across plasmalemma. Accumulating evidence indicates that neuronal SOCE (nSOCE) is inhibited in family AD (FAD) and the inhibition of which causes instability of dendritic spines and enhances amyloidogenesis. Mutant Presenilin fails to function as an ER calcium leak channel and promotes degradation of stromal interaction molecules (STIM), ER calcium sensors; these effects may account for the repression of nSOCE in FAD. We have demonstrated that activation of autophagy degrades STIM proteins, resulting in a trimming effect on a dendritic arbor, under proteasome inhibition and endoplasmic reticulum stress, which are intimately connected with AD. Thus, we hypothesize that autophagy represses SOCE by degrading STIM proteins, leading to synapse loss in AD. This review article will highlight the roles of SOCE in AD neurodegeneration, the degradative mechanisms of STIM protein, and the therapeutic potential and associated challenge.

Store-operated calcium entry compensates fast ER calcium loss in resting hippocampal neurons

Cell Calcium ◽  
2015 ◽  
Vol 58 (2) ◽  
pp. 147-159 ◽  
Author(s):  
Samira Samtleben ◽  
Britta Wachter ◽  
Robert Blum
Keyword(s):  
Hippocampal Neurons ◽  
Calcium Entry ◽  
Store Operated Calcium Entry ◽  
Calcium Loss ◽  
Er Calcium

scholarly journals Calcium Sensors STIM1 and STIM2 Regulate Different Calcium Functions in Cultured Hippocampal Neurons

2021 ◽  
Vol 12 ◽  
Author(s):  
Liliya Kushnireva ◽  
Eduard Korkotian ◽  
Menahem Segal
Keyword(s):  
Dendritic Spines ◽  
Hippocampal Neurons ◽  
Calcium Entry ◽  
Calcium Stores ◽  
Plastic Properties ◽  
Calcium Sensors ◽  
Central Neurons ◽  
Transient Rise ◽  
Store Operated Calcium Entry ◽  
Adult Neuron

There are growing indications for the involvement of calcium stores in the plastic properties of neurons and particularly in dendritic spines of central neurons. The store-operated calcium entry (SOCE) channels are assumed to be activated by the calcium sensor stromal interaction molecule (STIM)which leads to activation of its associated Orai channel. There are two STIM species, and the differential role of the two in SOCE is not entirely clear. In the present study, we were able to distinguish between transfected STIM1, which is more mobile primarily in young neurons, and STIM2 which is less mobile and more prominent in older neurons in culture. STIM1 mobility is associated with spontaneous calcium sparks, local transient rise in cytosolic [Ca2+]i, and in the formation and elongation of dendritic filopodia/spines. In contrast, STIM2 is associated with older neurons, where it is mobile and moves into dendritic spines primarily when cytosolic [Ca2+]i levels are reduced, apparently to activate resident Orai channels. These results highlight a role for STIM1 in the regulation of [Ca2+]i fluctuations associated with the formation of dendritic spines or filopodia in the developing neuron, whereas STIM2 is associated with the maintenance of calcium entry into stores in the adult neuron.

scholarly journals Synthesis and Pharmacological Characterization of 2-Aminoethyl Diphenylborinate (2-APB) Derivatives for Inhibition of Store-Operated Calcium Entry (SOCE) in MDA-MB-231 Breast Cancer Cells

2020 ◽  
Vol 21 (16) ◽  
pp. 5604 ◽  
Author(s):  
Achille Schild ◽  
Rajesh Bhardwaj ◽  
Nicolas Wenger ◽  
Dominic Tscherrig ◽  
Palanivel Kandasamy ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Endoplasmic Reticulum ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Structural Changes ◽  
Calcium Entry ◽  
Imaging Plate ◽  
Ip3 Receptors ◽  
Pharmacological Characterization ◽  
Store Operated Calcium Entry

Calcium ions regulate a wide array of physiological functions including cell differentiation, proliferation, muscle contraction, neurotransmission, and fertilization. The endoplasmic reticulum (ER) is the major intracellular Ca2+ store and cellular events that induce ER store depletion (e.g., activation of inositol 1,4,5-triphosphate (IP3) receptors) trigger a refilling process known as store-operated calcium entry (SOCE). It requires the intricate interaction between the Ca2+ sensing stromal interaction molecules (STIM) located in the ER membrane and the channel forming Orai proteins in the plasma membrane (PM). The resulting active STIM/Orai complexes form highly selective Ca2+ channels that facilitate a measurable Ca2+ influx into the cytosol followed by successive refilling of the ER by the sarcoplasmic/endoplasmic reticulum calcium ATPase (SERCA). STIM and Orai have attracted significant therapeutic interest, as enhanced SOCE has been associated with several cancers, and mutations in STIM and Orai have been linked to immunodeficiency, autoimmune, and muscular diseases. 2-Aminoethyl diphenylborinate (2-APB) is a known modulator and depending on its concentration can inhibit or enhance SOCE. We have synthesized several novel derivatives of 2-APB, introducing halogen and other small substituents systematically on each position of one of the phenyl rings. Using a fluorometric imaging plate reader (FLIPR) Tetra-based calcium imaging assay we have studied how these structural changes of 2-APB affect the SOCE modulation activity at different compound concentrations in MDA-MB-231 breast cancer cells. We have discovered 2-APB derivatives that block SOCE at low concentrations, at which 2-APB usually enhances SOCE.

scholarly journals The tethering function of mitofusin2 controls osteoclast differentiation by modulating the Ca2+–NFATc1 axis

2020 ◽  
Vol 295 (19) ◽  
pp. 6629-6640 ◽  
Author(s):  
Anna Ballard ◽  
Rong Zeng ◽  
Allahdad Zarei ◽  
Christine Shao ◽  
Linda Cox ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Bone Mass ◽  
Intracellular Signaling ◽  
Osteoclast Differentiation ◽  
Calcium Entry ◽  
Calcium Handling ◽  
Mitochondrial Network ◽  
Female Mice ◽  
Mitochondrial Functions ◽  
Store Operated Calcium Entry

Dynamic regulation of the mitochondrial network by mitofusins (MFNs) modulates energy production, cell survival, and many intracellular signaling events, including calcium handling. However, the relative importance of specific mitochondrial functions and their dependence on MFNs vary greatly among cell types. Osteoclasts have many mitochondria, and increased mitochondrial biogenesis and oxidative phosphorylation enhance bone resorption, but little is known about the mitochondrial network or MFNs in osteoclasts. Because expression of each MFN isoform increases with osteoclastogenesis, we conditionally deleted MFN1 and MFN2 (double conditional KO (dcKO)) in murine osteoclast precursors, finding that this increased bone mass in young female mice and abolished osteoclast precursor differentiation into mature osteoclasts in vitro. Defective osteoclastogenesis was reversed by overexpression of MFN2 but not MFN1; therefore, we generated mice lacking only MFN2 in osteoclasts. MFN2-deficient female mice had increased bone mass at 1 year and resistance to Receptor Activator of NF-κB Ligand (RANKL)-induced osteolysis at 8 weeks. To explore whether MFN-mediated tethering or mitophagy is important for osteoclastogenesis, we overexpressed MFN2 variants defective in either function in dcKO precursors and found that, although mitophagy was dispensable for differentiation, tethering was required. Because the master osteoclastogenic transcriptional regulator nuclear factor of activated T cells 1 (NFATc1) is calcium-regulated, we assessed calcium release from the endoplasmic reticulum and store-operated calcium entry and found that the latter was blunted in dcKO cells. Restored osteoclast differentiation by expression of intact MFN2 or the mitophagy-defective variant was associated with normalization of store-operated calcium entry and NFATc1 levels, indicating that MFN2 controls mitochondrion–endoplasmic reticulum tethering in osteoclasts.

scholarly journals Regulation of store-operated calcium entry during cell division

2012 ◽  
Vol 40 (1) ◽  
pp. 119-123 ◽  
Author(s):  
Jeremy T. Smyth ◽  
James W. Putney
Keyword(s):  
Endoplasmic Reticulum ◽  
Cell Division ◽  
Recent Work ◽  
Calcium Entry ◽  
Store Operated Calcium Entry ◽  
Dividing Cells ◽  
Complex Mechanisms ◽  
Molecular Components ◽  
Ca2 Channels

Store-operate Ca2+ channels gate Ca2+ entry into the cytoplasm in response to the depletion of Ca2+ from endoplasmic reticulum Ca2+ stores. The major molecular components of store-operated Ca2+ entry are STIM (stromal-interacting molecule) 1 (and in some instances STIM2) that serves as the endoplasmic reticulum Ca2+ sensor, and Orai (Orai1, Orai2 and Orai3) which function as pore-forming subunits of the store-operated channel. It has been known for some time that store-operated Ca2+ entry is shut down during cell division. Recent work has revealed complex mechanisms regulating the functions and locations of both STIM1 and Orai1 in dividing cells.

scholarly journals Impaired Store-Operated Calcium Entry and STIM1 Loss Lead to Reduced Insulin Secretion and Increased Endoplasmic Reticulum Stress in the Diabetic β-Cell

Diabetes ◽  
2018 ◽  
Vol 67 (11) ◽  
pp. 2293-2304 ◽  
Author(s):  
Tatsuyoshi Kono ◽  
Xin Tong ◽  
Solaema Taleb ◽  
Robert N. Bone ◽  
Hitoshi Iida ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Insulin Secretion ◽  
Endoplasmic Reticulum Stress ◽  
Calcium Entry ◽  
Β Cell ◽  
Store Operated Calcium Entry

scholarly journals Remodelling of the endoplasmic reticulum during store-operated calcium entry

2011 ◽  
Vol 103 (8) ◽  
pp. 365-380 ◽  
Author(s):  
Wei-Wei Shen ◽  
Maud Frieden ◽  
Nicolas Demaurex
Keyword(s):  
Endoplasmic Reticulum ◽  
Calcium Entry ◽  
Store Operated Calcium Entry

scholarly journals Store-operated calcium entry in physiology and pathology of mammalian cells.

2005 ◽  
Vol 52 (2) ◽  
pp. 397-409 ◽  
Author(s):  
Berenika Targos ◽  
Jolanta Barańska ◽  
Paweł Pomorski
Keyword(s):  
Cell Cycle ◽  
Calcium Level ◽  
Mammalian Cells ◽  
Long Term Potentiation ◽  
Calcium Entry ◽  
Neuroendocrine Cells ◽  
Calcium Stores ◽  
Excitable Cells ◽  
Store Operated Calcium Entry ◽  
Er Calcium

One of the numerous calcium-involving processes in mammalian cells is store-operated calcium entry (SOCE) -- the process in which depletion of calcium stores in the endoplasmic reticulum (ER) induces calcium influx from the extracellular space. Previously supposed to function only in non-excitable cells, SOCE is now known to play a role also in such excitable cells as neurons, muscles and neuroendocrine cells and is found in many different cell types. SOCE participates not only in processes dependent on ER calcium level but also specifically regulates some important processes such as cAMP production, T lymphocyte activation or induction of long-term potentiation. Impairment of SOCE can be an element of numerous disorders such as acute pancreatitis, primary immunodeficiency and, since it can take part in apoptosis or cell cycle regulation, SOCE may also be partially responsible for such serious disorders as Alzheimer disease and many types of cancer. Even disturbances in the 'servant' role of maintaining ER calcium level may cause serious effects because they can lead to ER homeostasis disturbance, influencing gene expression, protein synthesis and processing, and the cell cycle.

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