MASTER-NAADP: a membrane permeable precursor of the Ca mobilizing second messenger NAADP.

Upon stimulation of membrane receptors, nicotinic acid adenine dinucleotide phosphate (NAADP) is formed as second messenger within seconds and evokes Ca signaling in many different cell types. Here, to directly stimulate NAADP signaling, MASTER-NAADP, a Membrane permeAble, STabilized, bio-rEversibly pRotected precursor of NAADP is synthesized and release of its active NAADP mimetic, benzoic acid C-nucleoside, 2'-phospho-3'F-adenosine-diphosphate, by esterase digestion is confirmed. In the presence of NAADP receptor HN1L/JPT2 (hematological and neurological expressed 1-like protein, HN1L, also known as Jupiter microtubule-associated homolog 2, JPT2), this active NAADP mimetic releases Ca and increases the open probability of type 1 ryanodine receptor.

Ca puffs underlie adhesion-triggered Ca microdomains in T cells.

Ca signalling is pivotal in T cell activation, an essential process in adaptive immune responses. Key to this activation are Ca microdomains, which are transient increases in cytosolic Ca concentration occurring within narrow regions between the endoplasmic reticulum (ER) and the plasma membrane (PM), lasting a few tens of milliseconds. Adhesion Dependent Ca Microdomains (ADCM) rely on store-operated Ca entry (SOCE) via the ORAI/STIM system.

Generation and characterization of antagonistic anti-human CD39 nanobodies.

CD39 is the major enzyme controlling the levels of extracellular adenosine triphosphate (ATP) via the stepwise hydrolysis of ATP to adenosine diphosphate (ADP) and adenosine monophosphate (AMP). As extracellular ATP is a strong promoter of inflammation, monoclonal antibodies (mAbs) blocking CD39 are utilized therapeutically in the field of immune-oncology. Though anti-CD39 mAbs are highly specific for their target, they lack deep penetration into the dense tissue of solid tumors, due to their large size.

The TRPM2 ion channel regulates metabolic and thermogenic adaptations in adipose tissue of cold-exposed mice.

Introduction: During thermogenesis, adipose tissue (AT) becomes more active and enhances oxidative metabolism. The promotion of this process in white AT (WAT) is called "browning" and, together with the brown AT (BAT) activation, is considered as a promising approach to counteract obesity and metabolic diseases. Transient receptor potential cation channel, subfamily M, member 2 (TRPM2), is an ion channel that allows extracellular Ca influx into the cytosol, and is gated by adenosine diphosphate ribose (ADPR), produced from NAD degradation.

2'-deoxy-ADPR activates human TRPM2 faster than ADPR and thereby induces higher currents at physiological Ca concentrations.

TRPM2 is a Ca permeable, non-selective cation channel in the plasma membrane that is involved in the innate immune response regulating, for example, chemotaxis in neutrophils and cytokine secretion in monocytes and macrophages. The intracellular adenine nucleotides ADP-ribose (ADPR) and 2'-deoxy-ADPR (2dADPR) activate the channel, in combination with their co-agonist Ca. Interestingly, activation of human TRPM2 (hsTRPM2) by 2dADPR is much more effective than activation by ADPR.

DARTS: an open-source Python pipeline for Ca microdomain analysis in live cell imaging data.

Ca microdomains play a key role in intracellular signaling processes. For instance, they mediate the activation of T cells and, thus, the initial adaptive immune system. They are, however, also of utmost importance for activation of other cells, and a detailed understanding of the dynamics of these spatially localized Ca signals is crucial for a better understanding of the underlying signaling processes.

[iMED DENT-First in place model curriculum in dentistry in Germany].

October 2019 saw the launch of iMED DENT, the first model study program in dentistry in Germany. The launch was preceded by a development process lasting several years in which European locations, among others, with innovative dental study programs were initially visited. The central reform objective of the model study program was then defined: the development, implementation, and ongoing optimization of an interdisciplinary curriculum with a scientific focus that integrates theoretical and practical dental content.

T cell Ca microdomains through the lens of computational modeling.

Cellular Ca signaling is highly organized in time and space. Locally restricted and short-lived regions of Ca increase, called Ca microdomains, constitute building blocks that are differentially arranged to create cellular Ca signatures controlling physiological responses. Here, we focus on Ca microdomains occurring in restricted cytosolic spaces between the plasma membrane and the endoplasmic reticulum, called endoplasmic reticulum-plasma membrane junctions.

Short-term dietary changes can result in mucosal and systemic immune depression.

Omnivorous animals, including mice and humans, tend to prefer energy-dense nutrients rich in fat over plant-based diets, especially for short periods of time, but the health consequences of this short-term consumption of energy-dense nutrients are unclear. Here, we show that short-term reiterative switching to 'feast diets', mimicking our social eating behavior, breaches the potential buffering effect of the intestinal microbiota and reorganizes the immunological architecture of mucosa-associated lymphoid tissues. The first dietary switch was sufficient to induce transient mucosal immune depression and suppress systemic immunity, leading to higher susceptibility to Salmonella enterica serovar Typhimurium and Listeria monocytogenes infections.

Adhesion to laminin-1 and collagen IV induces the formation of Ca microdomains that sensitize mouse T cells for activation.

During an immune response, T cells migrate from blood vessel walls into inflamed tissues by migrating across the endothelium and through extracellular matrix (ECM). Integrins facilitate T cell binding to endothelial cells and ECM proteins. Here, we report that Ca microdomains observed in the absence of T cell receptor (TCR)/CD3 stimulation are initial signaling events triggered by adhesion to ECM proteins that increase the sensitivity of primary murine T cells to activation.

2-Methoxyestradiol-3,17-O,O-bis-sulfamate inhibits store-operated Ca entry in T lymphocytes and prevents experimental autoimmune encephalomyelitis.

Ca signaling is one of the essential signaling systems for T lymphocyte activation, the latter being an essential step in the pathogenesis of autoimmune diseases such as multiple sclerosis (MS). Store-operated Ca entry (SOCE) ensures long lasting Ca signaling and is of utmost importance for major downstream T lymphocyte activation steps, e.g.

Enzymology of Ca-Mobilizing Second Messengers Derived from NAD: From NAD Glycohydrolases to (Dual) NADPH Oxidases.

Nicotinamide adenine dinucleotide (NAD) and its 2'-phosphorylated cousin NADP are precursors for the enzymatic formation of the Ca-mobilizing second messengers adenosine diphosphoribose (ADPR), 2'-deoxy-ADPR, cyclic ADPR, and nicotinic acid adenine dinucleotide phosphate (NAADP). The enzymes involved are either NAD glycohydrolases CD38 or sterile alpha toll/interleukin receptor motif containing-1 (SARM1), or (dual) NADPH oxidases (NOX/DUOX). Enzymatic function(s) are reviewed and physiological role(s) in selected cell systems are discussed.

Tissue resident iNKT17 cells facilitate cancer cell extravasation in liver metastasis via interleukin-22.

During metastasis, cancer cells invade, intravasate, enter the circulation, extravasate, and colonize target organs. Here, we examined the role of interleukin (IL)-22 in metastasis. Immune cell-derived IL-22 acts on epithelial tissues, promoting regeneration and healing upon tissue damage, but it is also associated with malignancy.

Role of Liver CD38 in the Regulation of Metabolic Pathways during Cold-Induced Thermogenesis in Mice.

Boosting NAD levels are considered a promising means to promote healthy aging and ameliorate dysfunctional metabolism. The expression of CD38, the major NAD-consuming enzyme, is downregulated during thermogenesis in both brown and white adipose tissues (BAT and WAT). Moreover, BAT activation and WAT "browning" were enhanced in mice.

NAADP-Evoked Ca Signaling: The DUOX2-HN1L/JPT2-Ryanodine Receptor 1 Axis.

Nicotinic acid adenine dinucleotide phosphate (NAADP) is the most potent Ca mobilizing second messenger known to date. Major steps elucidating metabolism and Ca mobilizing activity of NAADP are reviewed, with emphasis on a novel redox cycle between the inactive reduced form, NAADPH, and the active oxidized form, NAADP. Oxidation from NAADPH to NAADP is catalyzed in cell free system by (dual) NADPH oxidases NOX5, DUOX1, and DUOX2, whereas reduction from NAADP to NAADPH is catalyzed by glucose 6-phosphate dehydrogenase.

P2X7 is expressed on human innate-like T lymphocytes and mediates susceptibility to ATP-induced cell death.

Extracellular ATP activates the P2X7 receptor, leading to inflammasome activation and release of pro-inflammatory cytokines in monocytes. However, a detailed analysis of P2X7 receptor expression and function in the human T cell compartment has not been reported. Here, we used a P2X7-specific nanobody to assess cell membrane expression and function of P2X7 on peripheral T lymphocyte subsets.

cADPR Does Not Activate TRPM2.

cADPR is a second messenger that releases Ca from intracellular stores via the ryanodine receptor. Over more than 15 years, it has been controversially discussed whether cADPR also contributes to the activation of the nucleotide-gated cation channel TRPM2. While some groups have observed activation of TRPM2 by cADPR alone or in synergy with ADPR, sometimes only at 37 °C, others have argued that this is due to the contamination of cADPR by ADPR.

NAADP Signaling: New Kids on the Block.

Nicotinic acid adenine dinucleotide phosphate (NAADP) is a universal Ca mobilizing second messenger essential for initiation of Ca signaling. Recently, novel molecular mechanisms of both its rapid formation upon receptor stimulation and its mode of action were discovered. Dual NADPH oxidase 2 (DUOX2) and hematological and neurological expressed 1-like protein (HN1L)/Jupiter microtubule-associated homolog 2 (JPT2) were discovered as NAADP-forming enzyme and NAADP receptor/binding protein-the new kids on the block.

Three-Dimensional Model of Sub-Plasmalemmal Ca Microdomains Evoked by T Cell Receptor/CD3 Complex Stimulation.

Ca signalling plays an essential role in T cell activation, which is a key step to start an adaptive immune response. During the transition from a quiescent to a fully activated state, Ca microdomains of reduced spatial and temporal extents develop in the junctions between the plasma membrane and the endoplasmic reticulum (ER). These microdomains rely on Ca entry from the extracellular medium, via the ORAI1/STIM1/STIM2 system that mediates store operated Ca entry Store operated calcium entry.

The calcium-sensing receptor stabilizes podocyte function in proteinuric humans and mice.

Calcimimetic agents allosterically increase the calcium ion sensitivity of the calcium-sensing receptor (CaSR), which is expressed in the tubular system and to a lesser extent in podocytes. Activation of this receptor can reduce glomerular proteinuria and structural damage in proteinuric animal models. However, the precise role of the podocyte CaSR remains unclear.

P2X4 and P2X7 are essential players in basal T cell activity and Ca signaling milliseconds after T cell activation.

Initial T cell activation is triggered by the formation of highly dynamic, spatiotemporally restricted Ca microdomains. Purinergic signaling is known to be involved in Ca influx in T cells at later stages compared to the initial microdomain formation. Using a high-resolution Ca live-cell imaging system, we show that the two purinergic cation channels P2X4 and P2X7 not only are involved in the global Ca signals but also promote initial Ca microdomains tens of milliseconds after T cell stimulation.

TRPM2 Is Not Required for T-Cell Activation and Differentiation.

Antigen recognition by the T-cell receptor induces a cytosolic Ca signal that is crucial for T-cell function. The Ca channel TRPM2 (transient receptor potential cation channel subfamily M member 2) has been shown to facilitate influx of extracellular Ca through the plasma membrane of T cells. Therefore, it was suggested that TRPM2 is involved in T-cell activation and differentiation.