scholarly journals Endoplasmic Reticulum-Based Calcium Dysfunctions in Synucleinopathies

2021 ◽  
Vol 12 ◽  
Author(s):  
Gergo Kovacs ◽  
Lasse Reimer ◽  
Poul Henning Jensen
Keyword(s):  
Endoplasmic Reticulum ◽  
Protective Factor ◽  
Calcium Influx ◽  
Cytosolic Calcium ◽  
Epidemiological Studies ◽  
Mechanistic Study ◽  
Basic Premise ◽  
C Elegans ◽  
Calcium Uniporter ◽  
Er Calcium

Neuronal calcium dyshomeostasis has been associated to Parkinson's disease (PD) development based on epidemiological studies on users of calcium channel antagonists and clinical trials are currently conducted exploring the hypothesis of increased calcium influx into neuronal cytosol as basic premise. We reported in 2018 an opposite hypothesis based on the demonstration that α-synuclein aggregates stimulate the endoplasmic reticulum (ER) calcium pump SERCA and demonstrated in cell models the existence of an α-synuclein-aggregate dependent neuronal state wherein cytosolic calcium is decreased due to an increased pumping of calcium into the ER. Inhibiting the SERCA pump protected both neurons and an α-synuclein transgenic C. elegans model. This models two cellular states that could contribute to development of PD. First the prolonged state with reduced cytosolic calcium that could deregulate multiple signaling pathways. Second the disease ER state with increased calcium concentration. We will discuss our hypothesis in the light of recent papers. First, a mechanistic study describing how variation in the Inositol-1,4,5-triphosphate (IP3) kinase B (ITPKB) may explain GWAS studies identifying the ITPKB gene as a protective factor toward PD. Here it was demonstrated that how increased ITPKB activity reduces influx of ER calcium to mitochondria via contact between IP3-receptors and the mitochondrial calcium uniporter complex in ER-mitochondria contact, known as mitochondria-associated membranes (MAMs). Secondly, it was demonstrated that astrocytes derived from PD patients contain α-synuclein accumulations. A recent study has demonstrated how human astrocytes derived from a few PD patients carrying the LRRK2-2019S mutation express more α-synuclein than control astrocytes, release more calcium from ER upon ryanodine receptor (RyR) stimulation, show changes in ER calcium channels and exhibit a decreased maximal and spare respiration indicating altered mitochondrial function in PD astrocytes. Here, we summarize the previous findings focusing the effect of α-synuclein to SERCA, RyR, IP3R, MCU subunits and other MAM-related channels. We also consider how the SOCE-related events could contribute to the development of PD.

Calcium entry, mobilization, and extrusion in postcapillary venular endothelium exposed to bradykinin

1993 ◽  
Vol 265 (2) ◽  
pp. H569-H580 ◽  
Author(s):  
M. Ziche ◽  
D. Zawieja ◽  
R. K. Hester ◽  
H. Granger
Keyword(s):  
Endoplasmic Reticulum ◽  
Intracellular Calcium ◽  
Calcium Concentration ◽  
Calcium Influx ◽  
Cytosolic Calcium ◽  
Calcium Pump ◽  
Endoplasmic Reticulum Calcium ◽  
Calcium Indicator ◽  
Subsequent Exposure ◽  
Calcium Extrusion

The effect of bradykinin (BK) on cytosolic calcium in coronary venular endothelial cells (CVEC) was studied using the intracellular calcium indicator indo 1. At normal extracellular calcium levels, CVEC responded to BK at concentrations as low as 0.1 pM; maximum cytosolic calcium spikes occurred at 10 nM. In calcium-free medium, poststimulation cytosolic calcium concentration returned to levels below prestimulation values, implying that BK modulates calcium extrusion mechanisms that are normally masked by calcium influx into the cell. To test this hypothesis, we depleted internal stores of calcium using two approaches: preconditioning or blockade of the endoplasmic reticulum calcium pump with the sesquiterpene lactone, thapsigargin. Depletion by preconditioning consisted of two prior doses of BK followed by a third stimulus of the agonist. Under these conditions, the final dose of BK caused a fall, rather than rise, in cytosolic calcium. Thapsigargin blocked the endoplasmic reticulum calcium pump, leading to a steady-state rise in intracellular calcium concentration. Subsequent exposure of these cells to BK also led to a fall in cytosolic calcium. The preconditioning and thapsigargin studies are consistent with a modulation of calcium extrusion processes by BK in CVEC. The signals responsible for this modulation are unknown.

scholarly journals Sorcin is an early marker of neurodegeneration, Ca2+ dysregulation and endoplasmic reticulum stress associated to neurodegenerative diseases

2020 ◽  
Vol 11 (10) ◽  
Author(s):  
Ilaria Genovese ◽  
Flavia Giamogante ◽  
Lucia Barazzuol ◽  
Theo Battista ◽  
Annarita Fiorillo ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Neurodegenerative Diseases ◽  
Calcium Binding ◽  
Cytosolic Calcium ◽  
Sigma 1 Receptor ◽  
Calcium Dependent ◽  
Early Marker ◽  
Sigma 1 ◽  
Stress Dependent ◽  
Er Calcium

Abstract Dysregulation of calcium signaling is emerging as a key feature in the pathogenesis of neurodegenerative diseases such as Alzheimer’s disease (AD), Parkinson’s disease (PD), and Huntington’s disease (HD), and targeting this process may be therapeutically beneficial. Under this perspective, it is important to study proteins that regulate calcium homeostasis in the cell. Sorcin is one of the most expressed calcium-binding proteins in the human brain; its overexpression increases endoplasmic reticulum (ER) calcium concentration and decreases ER stress in the heart and in other cellular types. Sorcin has been hypothesized to be involved in neurodegenerative diseases, since it may counteract the increased cytosolic calcium levels associated with neurodegeneration. In the present work, we show that Sorcin expression levels are strongly increased in cellular, animal, and human models of AD, PD, and HD, vs. normal cells. Sorcin partially colocalizes with RyRs in neurons and microglia cells; functional experiments with microsomes containing high amounts of RyR2 and RyR3, respectively, show that Sorcin is able to regulate these ER calcium channels. The molecular basis of the interaction of Sorcin with RyR2 and RyR3 is demonstrated by SPR. Sorcin also interacts with other ER proteins as SERCA2 and Sigma-1 receptor in a calcium-dependent fashion. We also show that Sorcin regulates ER calcium transients: Sorcin increases the velocity of ER calcium uptake (increasing SERCA activity). The data presented here demonstrate that Sorcin may represent both a novel early marker of neurodegenerative diseases and a response to cellular stress dependent on neurodegeneration.

2,3,7,8-Tetrachlorodibenzo-p-Dioxin (TCDD) Induces Calcium Influx Through T-type Calcium Channel and Enhances Lysosomal Exocytosis and Insulin Secretion in INS-1 Cells

2009 ◽  
Vol 28 (3) ◽  
pp. 151-161 ◽  
Author(s):  
Youn-Hee Kim ◽  
Young-Jun Shim ◽  
Yong-Jae Shin ◽  
Donggeun Sul ◽  
Eunil Lee ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Beta Cell ◽  
Calcium Channel ◽  
Calcium Influx ◽  
Cytosolic Calcium ◽  
Epidemiological Studies ◽  
Channel Blockers ◽  
Aryl Hydrocarbon ◽  
Beta Cell Line ◽  
Tetrachlorodibenzo P Dioxin

2,3,7,8-Tetrachlorodibenzo- p-dioxin (TCDD) has been associated with diabetes in several epidemiological studies. However, the diabetogenic action of TCDD on pancreatic cells is unclear. Here, we investigated the direct toxic effects of TCDD on a rat insulin-secreting beta cell line. We found that TCDD enhances exocytosis of MTT formazan and lysosomal proteins such as β-hexosaminindase and Lamp-1. This TCDD-induced exocytosis was abrogated by T-type calcium channel blockers (mibefradil, flunarizine) but not by an aryl hydrocarbon receptor antagonist (α-naphtoflavone). Indeed, cytosolic calcium levels were increased by TCDD. Furthermore, TCDD stimulated insulin secretion, which was inhibited by flunarizine. Taken together, our results suggest that TCDD-induced calcium influx via T-type channels regulates vesicular trafficking, such as lysosomal and secretory granule exocytosis, and that TCDD might exert adverse effects on beta cells by continuous insulin release followed by beta cell exhaustion. This could contribute to the link between TCDD exposure and the risk of developing diabetes.

scholarly journals Endoplasmic reticulum generates calcium signalling microdomains around the nucleus and spindle in syncytial Drosophila embryos

2006 ◽  
Vol 34 (3) ◽  
pp. 385-388 ◽  
Author(s):  
H. Parry ◽  
A. McDougall ◽  
M. Whitaker
Keyword(s):  
Endoplasmic Reticulum ◽  
Mitotic Spindle ◽  
Spatial Organization ◽  
Calcium Influx ◽  
Calcium Signalling ◽  
Calcium Transients ◽  
Calcium Store ◽  
Internal Calcium ◽  
Er Calcium ◽  
Drosophila Embryos

Cell cycle calcium signals are generated by inositol trisphosphate-mediated release of calcium from internal stores [Ciapa, Pesando, Wilding and Whitaker (1994) Nature (London) 368, 875–878; Groigno and Whitaker (1998) Cell 92, 193–204]. The major internal calcium store is the ER (endoplasmic reticulum): the spatial organization of the ER during mitosis is important in defining a microdomain around the nucleus and mitotic spindle in early Drosophila embryos [Parry, McDougall and Whitaker (2005) J. Cell Biol. 171, 47–59]. Nuclear divisions in syncytial Drosophila embryos are accompanied by both cortical and nuclear localized calcium transients. Mitosis is prevented by the InsP3 antagonists Xestospongin C and heparin. Nuclear-localized transients and cortical transients rely on extraembryonic calcium, suggesting that ER calcium levels are maintained by calcium influx.

scholarly journals Discovery of endoplasmic reticulum calcium stabilizers to rescue ER-stressed podocytes in nephrotic syndrome

2019 ◽  
Vol 116 (28) ◽  
pp. 14154-14163 ◽  
Author(s):  
Sun-Ji Park ◽  
Yeawon Kim ◽  
Shyh-Ming Yang ◽  
Mark J. Henderson ◽  
Wei Yang ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Nephrotic Syndrome ◽  
Er Stress ◽  
Calcium Release ◽  
Cytosolic Calcium ◽  
Calcium Release Channel ◽  
Release Channel ◽  
Podocyte Injury ◽  
Endoplasmic Reticulum Calcium ◽  
Er Calcium

Emerging evidence has established primary nephrotic syndrome (NS), including focal segmental glomerulosclerosis (FSGS), as a primary podocytopathy. Despite the underlying importance of podocyte endoplasmic reticulum (ER) stress in the pathogenesis of NS, no treatment currently targets the podocyte ER. In our monogenic podocyte ER stress-induced NS/FSGS mouse model, the podocyte type 2 ryanodine receptor (RyR2)/calcium release channel on the ER was phosphorylated, resulting in ER calcium leak and cytosolic calcium elevation. The altered intracellular calcium homeostasis led to activation of calcium-dependent cytosolic protease calpain 2 and cleavage of its important downstream substrates, including the apoptotic molecule procaspase 12 and podocyte cytoskeletal protein talin 1. Importantly, a chemical compound, K201, can block RyR2-Ser2808 phosphorylation-mediated ER calcium depletion and podocyte injury in ER-stressed podocytes, as well as inhibit albuminuria in our NS model. In addition, we discovered that mesencephalic astrocyte-derived neurotrophic factor (MANF) can revert defective RyR2-induced ER calcium leak, a bioactivity for this ER stress-responsive protein. Thus, podocyte RyR2 remodeling contributes to ER stress-induced podocyte injury. K201 and MANF could be promising therapies for the treatment of podocyte ER stress-induced NS/FSGS.

scholarly journals Alternative redox forms of ASNA-1 separate insulin signaling from tail-anchored protein targeting and cisplatin resistance in C. elegans

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Dorota Raj ◽  
Ola Billing ◽  
Agnieszka Podraza-Farhanieh ◽  
Bashar Kraish ◽  
Oskar Hemmingsson ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Insulin Secretion ◽  
Protein Targeting ◽  
Cisplatin Resistance ◽  
Acquired Resistance ◽  
Endoplasmic Reticulum Membrane ◽  
C Elegans ◽  
Cisplatin Sensitivity ◽  
Tumor Environment ◽  
The One

AbstractCisplatin is a frontline cancer therapeutic, but intrinsic or acquired resistance is common. We previously showed that cisplatin sensitivity can be achieved by inactivation of ASNA-1/TRC40 in mammalian cancer cells and in Caenorhabditis elegans. ASNA-1 has two more conserved functions: in promoting tail-anchored protein (TAP) targeting to the endoplasmic reticulum membrane and in promoting insulin secretion. However, the relation between its different functions has remained unknown. Here, we show that ASNA-1 exists in two redox states that promote TAP-targeting and insulin secretion separately. The reduced state is the one required for cisplatin resistance: an ASNA-1 point mutant, in which the protein preferentially was found in the oxidized state, was sensitive to cisplatin and defective for TAP targeting but had no insulin secretion defect. The same was true for mutants in wrb-1, which we identify as the C. elegans homolog of WRB, the ASNA1/TRC40 receptor. Finally, we uncover a previously unknown action of cisplatin induced reactive oxygen species: cisplatin induced ROS drives ASNA-1 into the oxidized form, and selectively prevents an ASNA-1-dependent TAP substrate from reaching the endoplasmic reticulum. Our work suggests that ASNA-1 acts as a redox-sensitive target for cisplatin cytotoxicity and that cisplatin resistance is likely mediated by ASNA-1-dependent TAP substrates. Treatments that promote an oxidizing tumor environment should be explored as possible means to combat cisplatin resistance.

Sevoflurane but not propofol provided dual effects of cell survival in human neuroblastoma SH-SY5Y cells

2021 ◽  
Vol 18 ◽  
Author(s):  
Xue Gao ◽  
Xiu Wang ◽  
Lei Zhang ◽  
Ge Liang ◽  
Rachel Mund ◽  
...  
Keyword(s):  
Cell Survival ◽  
Prolonged Exposure ◽  
Calcium Influx ◽  
Cell Damage ◽  
Cytosolic Calcium ◽  
Extracellular Calcium ◽  
Mitochondrial Calcium ◽  
General Anesthetics ◽  
Wild Type ◽  
Human Neuroblastoma

Background: We have hypothesized that the most commonly used intravenous (propofol) and inhalational (sevoflurane) general anesthetics affect cell survival concentration and duration dependently with different potency associated with their differential potency to affect intracellular calcium homeostasis. Methods: Human neuroblastoma SH-SY5Y cells stably transfected with either wild type or M146L mutant human presenilin 1 were cultured and exposed to equipotent of propofol or sevoflurane. Cell viability, cytosolic and mitochondrial calcium were measured. Results: Sevoflurane but not propofol, at clinically relevant concentrations and durations, promoted cell survival. Prolonged exposure (24 hours) of 1% sevoflurane resulted in significant cell damage in both types of cells. Both sevoflurane and propofol had significantly higher cell response rates to the elevation of cytosolic calcium or mitochondrial calcium in the presence of extracellular calcium. With the contribution of calcium influx, sevoflurane but not equipotent 1 MAC propofol, caused a significantly greater increase in peak and overall calcium in Alzheimer’s mutation cell than in wild type cells, but significantly more increase in overall mitochondrial calcium concentrations in wild type than mutation cells. In the absence of extracellular calcium influx, sevoflurane, but not propofol, caused more significant elevations of overall mitochondrial calcium concentration in mutation cells than control cells. Conclusion: Calcium influx contributed to the general anesthetics mediated elevation of cytosolic or mitochondrial calcium, which is especially true for propofol. Sevoflurane has a greater potency to either promote or inhibit cell survival than propofol, which may be associated with its ability to affect cytosolic or mitochondrial calcium.

scholarly journals Dietary patterns and CVD: a systematic review and meta-analysis of observational studies

2015 ◽  
Vol 114 (9) ◽  
pp. 1341-1359 ◽  
Author(s):  
Míriam Rodríguez-Monforte ◽  
Gemma Flores-Mateo ◽  
Emília Sánchez
Keyword(s):  
Cohort Studies ◽  
Dietary Patterns ◽  
Observational Studies ◽  
Protective Factor ◽  
Meta Analysis ◽  
Epidemiological Studies ◽  
Case Control ◽  
Case Control Studies ◽  
Chd Risk ◽  
Control Comparison

AbstractEpidemiological studies show that diet is linked to the risk of developing CVD. The objective of this meta-analysis was to estimate the association between empirically derived dietary patterns and CVD. PubMed was searched for observational studies of data-driven dietary patterns that reported outcomes of cardiovascular events. The association between dietary patterns and CVD was estimated using a random-effects meta-analysis with 95 % CI. Totally, twenty-two observational studies met the inclusion criteria. The pooled relative risk (RR) for CVD, CHD and stroke in a comparison of the highest to the lowest category of prudent/healthy dietary patterns in cohort studies was 0·69 (95 % CI 0·60, 0·78; I2=0 %), 0·83 (95 % CI 0·75, 0·92; I2=44·6 %) and 0·86 (95 % CI 0·74, 1·01; I2=59·5 %), respectively. The pooled RR of CHD in a case–control comparison of the highest to the lowest category of prudent/healthy dietary patterns was 0·71 (95 % CI 0·63, 0·80; I2=0 %). The pooled RR for CVD, CHD and stroke in a comparison of the highest to the lowest category of western dietary patterns in cohort studies was 1·14 (95 % CI 0·92, 1·42; I2=56·9 %), 1·03 (95 % CI 0·90, 1·17; I2=59·4 %) and 1·05 (95 % CI 0·91, 1·22; I2=27·6 %), respectively; in case–control studies, there was evidence of increased CHD risk. Our results support the evidence of the prudent/healthy pattern as a protective factor for CVD.

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