Purinergic receptor P2X7 regulates interleukin-1α mediated inflammation in chronic kidney disease in a reactive oxygen species-dependent manner.

Onset, progression and cardiovascular outcome of chronic kidney disease (CKD) are influenced by the concomitant sterile inflammation. The pro-inflammatory cytokine family interleukin (IL)-1 is crucial in CKD with the key alarmin IL-1α playing an additional role as an adhesion molecule that facilitates immune cell tissue infiltration and consequently inflammation. Here, we investigate calcium ion and reactive oxygen species (ROS)-dependent regulation of different aspects of IL-1α-mediated inflammation.

Acute Downregulation but Not Genetic Ablation of Murine MCU Impairs Suppressive Capacity of Regulatory CD4 T Cells.

By virtue of mitochondrial control of energy production, reactive oxygen species (ROS) generation, and maintenance of Ca homeostasis, mitochondria play an essential role in modulating T cell function. The mitochondrial Ca uniporter (MCU) is the pore-forming unit in the main protein complex mediating mitochondrial Ca uptake. Recently, MCU has been shown to modulate Ca signals at subcellular organellar interfaces, thus fine-tuning NFAT translocation and T cell activation.

Store-operated calcium entry is reduced in spastin-linked hereditary spastic paraplegia.

Pathogenic variants in SPAST, the gene coding for spastin, are the single most common cause of hereditary spastic paraplegia, a progressive motor neuron disease. Spastin regulates key cellular functions, including microtubule-severing and endoplasmic reticulum-morphogenesis. However, it remains unclear how alterations in these cellular functions due to SPAST pathogenic variants result in motor neuron dysfunction.

X-ray irradiation triggers immune response in human T-lymphocytes via store-operated Ca2+ entry and NFAT activation.

Radiation therapy efficiently eliminates cancer cells and reduces tumor growth. To understand collateral agonistic and antagonistic effects of this treatment on the immune system, we examined the impact of x-ray irradiation on human T cells. We find that, in a major population of leukemic Jurkat T cells and peripheral blood mononuclear cells, clinically relevant radiation doses trigger delayed oscillations of the cytosolic Ca2+ concentration.

On the Connections between TRPM Channels and SOCE.

Plasma membrane protein channels provide a passageway for ions to access the intracellular milieu. Rapid entry of calcium ions into cells is controlled mostly by ion channels, while Ca-ATPases and Ca exchangers ensure that cytosolic Ca levels ([Ca]) are maintained at low (~100 nM) concentrations. Some channels, such as the Ca-release-activated Ca (CRAC) channels and voltage-dependent Ca channels (CACNAs), are highly Ca-selective, while others, including the Transient Receptor Potential Melastatin (TRPM) family, have broader selectivity and are mostly permeable to monovalent and divalent cations.

A longer isoform of Stim1 is a negative SOCE regulator but increases cAMP-modulated NFAT signaling.

Alternative splicing is a potent modifier of protein function. Stromal interaction molecule 1 (Stim1) is the essential activator of store-operated Ca entry (SOCE) triggering activation of transcription factors. Here, we characterize Stim1A, a splice variant with an additional 31 amino acid domain inserted in frame within its cytosolic domain.

Remodelling of Ca homeostasis is linked to enlarged endoplasmic reticulum in secretory cells.

The endoplasmic reticulum (ER) is extensively remodelled during the development of professional secretory cells to cope with high protein production. Since ER is the principal Ca store in the cell, we characterised the Ca homeostasis in NALM-6 and RPMI 8226 cells, which are commonly used as human pre-B and antibody secreting plasma cell models, respectively. Expression levels of Sec61 translocons and the corresponding Sec61-mediated Ca leak from ER, Ca storage capacity and store-operated Ca entry were significantly enlarged in the secretory RPMI 8226 cell line.

Interleukin-1α Is a Central Regulator of Leukocyte-Endothelial Adhesion in Myocardial Infarction and in Chronic Kidney Disease.

Background: Cardiovascular diseases and chronic kidney disease (CKD) are highly prevalent, aggravate each other, and account for substantial mortality. Both conditions are characterized by activation of the innate immune system. The alarmin interleukin-1α (IL-1α) is expressed in a variety of cell types promoting (sterile) systemic inflammation.

Plasma Membrane Calcium ATPase Regulates Stoichiometry of CD4 T-Cell Compartments.

Immune responses involve mobilization of T cells within naïve and memory compartments. Tightly regulated Ca levels are essential for balanced immune outcomes. How Ca contributes to regulating compartment stoichiometry is unknown.

Genetically determined NLRP3 inflammasome activation associates with systemic inflammation and cardiovascular mortality.

Aims: Inflammation plays an important role in cardiovascular disease (CVD) development. The NOD-like receptor protein-3 (NLRP3) inflammasome contributes to the development of atherosclerosis in animal models. Components of the NLRP3 inflammasome pathway such as interleukin-1β can therapeutically be targeted.

A short isoform of STIM1 confers frequency-dependent synaptic enhancement.

Store-operated Ca-entry (SOCE) regulates basal and receptor-triggered Ca signaling with STIM proteins sensing the endoplasmic reticulum (ER) Ca content and triggering Ca entry by gating Orai channels. Although crucial for immune cells, STIM1's role in neuronal Ca homeostasis is controversial. Here, we characterize a splice variant, STIM1B, which shows exclusive neuronal expression and protein content surpassing conventional STIM1 in cerebellum and of significant abundance in other brain regions.

Supra-Molecular Assemblies of ORAI1 at Rest Precede Local Accumulation into Puncta after Activation.

The Ca selective channel ORAI1 and endoplasmic reticulum (ER)-resident STIM proteins form the core of the channel complex mediating store operated Ca entry (SOCE). Using liquid phase electron microscopy (LPEM), the distribution of ORAI1 proteins was examined at rest and after SOCE-activation at nanoscale resolution. The analysis of over seven hundred thousand ORAI1 positions revealed a number of ORAI1 channels had formed STIM-independent distinct supra-molecular clusters.

TRICking SOCE into altered oscillations.

Defective ER/SR-cytosol Ca cycling is associated with increased ER stress, pathological heart conditions and muscular defects. Within the SR, ryanodine receptor 2 (RyR2) is required for excitation/contraction coupling. Ca release from the SR is counterbalanced by K influx through trimeric intracellular cation (TRIC) channels to maintain ER/SR polarity.

High glucose distinctively regulates Ca influx in cytotoxic T lymphocytes upon target recognition and thapsigargin stimulation.

In CTLs: High glucose-culture enhances thapsigargin-induced SOCE but decreases target recognition-induced Ca influx. High glucose-culture regulates expression of ORAIs and STIMs without affecting glucose uptake. More high glucose-cultured CTLs are prone to necrosis after execution of killing.

The impact of capsaicinoids on APP processing in Alzheimer's disease in SH-SY5Y cells.

The vanilloid capsaicin is a widely consumed spice, known for its burning and "hot" sensation through activation of TRPV1 ion-channels, but also known to decrease oxidative stress, inflammation and influence tau-pathology. Beside these positive effects, little is known about its effects on amyloid-precursor-protein (APP) processing leading to amyloid-β (Aβ), the major component of senile plaques. Treatment of neuroblastoma cells with capsaicinoids (24 hours, 10 µM) resulted in enhanced Aβ-production and reduced Aβ-degradation, leading to increased Aβ-levels.

Detecting single ORAI1 proteins within the plasma membrane reveals higher-order channel complexes.

ORAI1 proteins form highly selective Ca channels in the plasma membrane. Crystallographic data point towards a hexameric stoichiometry of ORAI1 channels, whereas optical methods postulated ORAI1 channels to reside as dimers at rest, and other data suggests that they have a tetrameric configuration. Here, liquid-phase scanning transmission electron microscopy (STEM) and quantum dot (QD) labeling was utilized to study the conformation of ORAI1 proteins at rest.

Apolipoprotein C3 induces inflammation and organ damage by alternative inflammasome activation.

NLRP3-inflammasome-driven inflammation is involved in the pathogenesis of a variety of diseases. Identification of endogenous inflammasome activators is essential for the development of new anti-inflammatory treatment strategies. Here, we identified that apolipoprotein C3 (ApoC3) activates the NLRP3 inflammasome in human monocytes by inducing an alternative NLRP3 inflammasome via caspase-8 and dimerization of Toll-like receptors 2 and 4.

Expression of the LRRC52 γ subunit (γ2) may provide Ca-independent activation of BK currents in mouse inner hair cells.

Mammalian inner hair cells (IHCs) transduce sound into depolarization and transmitter release. Big conductance and voltage- and Ca-activated K (BK) channels are responsible for fast membrane repolarization and small time constants of mature IHCs. For unknown reasons, they activate at around -75 mV with a voltage of half-maximum activation () of -50 mV although being largely insensitive to Ca influx.

Redox signals at the ER-mitochondria interface control melanoma progression.

Reactive oxygen species (ROS) are emerging as important regulators of cancer growth and metastatic spread. However, how cells integrate redox signals to affect cancer progression is not fully understood. Mitochondria are cellular redox hubs, which are highly regulated by interactions with neighboring organelles.

Stepping out of the shadow: STIM2 promotes IL-3-induced cytokine release.

Basophils are a small population of innate immune cells, but their release of the cytokine interleukin-4 (IL-4) is important for mounting an efficient immune response against distinct parasites. Yoshikawa (in the 9 April 2019 issue) showed that whereas STIM1 is essential for IL-4 release after stimulation of FcεRI, STIM2 mediates a delayed IL-3/IL-33-induced IL-4 release independent of STIM1.

Reaction-diffusion model for STIM-ORAI interaction: The role of ROS and mutations.

Release of Ca from endoplasmatic retriculum (ER) Ca stores causes stromal interaction molecules (STIM) in the ER membrane and ORAI proteins in the plasma membrane (PM) to interact and form the Ca release activated Ca (CRAC) channels, which represent a major Ca entry route in non-excitable cells and thus control various cell functions. It is experimentally possible to mutate ORAI1 proteins and therefore modify, especially block, the Ca influx into the cell. On the basis of the model of Hoover and Lewis (2011), we formulate a reaction-diffusion model to quantify the STIM1-ORAI1 interaction during CRAC channel formation and analyze different ORAI1 channel stoichiometries and different ratios of STIM1 and ORAI1 in comparison with experimental data.

Pyrtriazoles, a Novel Class of Store-Operated Calcium Entry Modulators: Discovery, Biological Profiling, and in Vivo Proof-of-Concept Efficacy in Acute Pancreatitis.

In recent years, channels that mediate store-operated calcium entry (SOCE, i.e., the ability of cells to sense a decrease in endoplasmic reticulum luminal calcium and induce calcium entry across the plasma membrane) have been associated with a number of disorders, spanning from immune disorders to acute pancreatitis and have been suggested to be druggable targets.