Abstract:Background. Asthma is a disease with a core abnormality in airway smooth muscle function, and the proliferation of airway smooth muscle cells (ASMCs) plays a pivotal role in asthma airway remodeling. Our previous study showed that S100A9 (S100 calcium-binding protein A9; 400 and 800 ng/mL) significantly inhibited rat ASMCs proliferation at 48 h, and 50–800 ng/mL S100A9 (50, 100, 200, 400, and 800 ng/mL) also induced a lasting effect by significantly inhibiting rat ASMCs proliferation at 72 h in a dose-dependen… Show more
“…7m, n), consistent with the impact on S100A9 expression of reduced Ca 2+ flux through RyRs (Fig. 5i, j) and previous reports on S100A9 repression during proliferation of airway smooth muscles 57 . These observations, the distribution of chromatin marks and general tendency of NE-association to keep chromatin repressed 58,59 lends support to the view that NE invaginations may play a role in genome regulation and cycles of gene repression and activation.Fig.…”
Ca
2+
coordinates diverse cellular processes, yet how function-specific signals arise is enigmatic. We describe a cell-wide network of distinct cytoplasmic nanocourses with the nucleus at its centre, demarcated by sarcoplasmic reticulum (SR) junctions (≤400 nm across) that restrict Ca
2+
diffusion and by nanocourse-specific Ca
2+
-pumps that facilitate signal segregation. Ryanodine receptor subtype 1 (RyR1) supports relaxation of arterial myocytes by unloading Ca
2+
into peripheral nanocourses delimited by plasmalemma-SR junctions, fed by sarco/endoplasmic reticulum Ca
2+
ATPase 2b (SERCA2b). Conversely, stimulus-specified increases in Ca
2+
flux through RyR2/3 clusters selects for rapid propagation of Ca
2+
signals throughout deeper extraperinuclear nanocourses and thus myocyte contraction. Nuclear envelope invaginations incorporating SERCA1 in their outer nuclear membranes demarcate further diverse networks of cytoplasmic nanocourses that receive Ca
2+
signals through discrete RyR1 clusters, impacting gene expression through epigenetic marks segregated by their associated invaginations. Critically, this circuit is not hardwired and remodels for different outputs during cell proliferation.
“…7m, n), consistent with the impact on S100A9 expression of reduced Ca 2+ flux through RyRs (Fig. 5i, j) and previous reports on S100A9 repression during proliferation of airway smooth muscles 57 . These observations, the distribution of chromatin marks and general tendency of NE-association to keep chromatin repressed 58,59 lends support to the view that NE invaginations may play a role in genome regulation and cycles of gene repression and activation.Fig.…”
Ca
2+
coordinates diverse cellular processes, yet how function-specific signals arise is enigmatic. We describe a cell-wide network of distinct cytoplasmic nanocourses with the nucleus at its centre, demarcated by sarcoplasmic reticulum (SR) junctions (≤400 nm across) that restrict Ca
2+
diffusion and by nanocourse-specific Ca
2+
-pumps that facilitate signal segregation. Ryanodine receptor subtype 1 (RyR1) supports relaxation of arterial myocytes by unloading Ca
2+
into peripheral nanocourses delimited by plasmalemma-SR junctions, fed by sarco/endoplasmic reticulum Ca
2+
ATPase 2b (SERCA2b). Conversely, stimulus-specified increases in Ca
2+
flux through RyR2/3 clusters selects for rapid propagation of Ca
2+
signals throughout deeper extraperinuclear nanocourses and thus myocyte contraction. Nuclear envelope invaginations incorporating SERCA1 in their outer nuclear membranes demarcate further diverse networks of cytoplasmic nanocourses that receive Ca
2+
signals through discrete RyR1 clusters, impacting gene expression through epigenetic marks segregated by their associated invaginations. Critically, this circuit is not hardwired and remodels for different outputs during cell proliferation.
“…These observations are therefore consistent with the idea that invaginations act to regulate anti-proliferative genes, that is until the proliferative phenotype [ 219 ] is ready to be engaged. During proliferation we noted loss of S100A9 expression (but not MLH1 expression), namely the emerin and BAF regulated gene whose expression was attenuated by blocking calcium flux through RyRs with tetracaine, which is consistent with previous reports on S100A9 repression during proliferation of airway smooth muscles [ 220 ]. These observations, the distribution of chromatin marks and general tendency of NE-association to keep chromatin repressed [ 221 , 222 ] lends support to the view that NE invaginations may play a role in genome regulation and cycles of gene repression and activation.…”
Section: More Than This: Lost In Proliferationsupporting
A plethora of cellular functions are controlled by calcium signals, that are greatly coordinated by calcium release from intracellular stores, the principal component of which is the sarco/endooplasmic reticulum (S/ER). In 1997 it was generally accepted that activation of various G protein-coupled receptors facilitated inositol-1,4,5-trisphosphate (IP3) production, activation of IP3 receptors and thus calcium release from S/ER. Adding to this, it was evident that S/ER resident ryanodine receptors (RyRs) could support two opposing cellular functions by delivering either highly localised calcium signals, such as calcium sparks, or by carrying propagating, global calcium waves. Coincidentally, it was reported that RyRs in mammalian cardiac myocytes might be regulated by a novel calcium mobilising messenger, cyclic adenosine diphosphate-ribose (cADPR), that had recently been discovered by HC Lee in sea urchin eggs. A reputedly selective and competitive cADPR antagonist, 8‑bromo‑cADPR, had been developed and was made available to us. We used 8‑bromo‑cADPR to further explore our observation that S/ER calcium release via RyRs could mediate two opposing functions, namely pulmonary artery dilation and constriction, in a manner seemingly independent of IP3Rs or calcium influx pathways. Importantly, the work of others had shown that, unlike skeletal and cardiac muscles, smooth muscles might express all three RyR subtypes. If this were the case in our experimental system and cADPR played a role, then 8‑bromo‑cADPR would surely block one of the opposing RyR-dependent functions identified, or the other, but certainly not both. The latter seemingly implausible scenario was confirmed. How could this be, do cells hold multiple, segregated SR stores that incorporate different RyR subtypes in receipt of spatially segregated signals carried by cADPR? The pharmacological profile of 8‑bromo‑cADPR action supported not only this, but also indicated that intracellular calcium signals were delivered across intracellular junctions formed by the S/ER. Not just one, at least two. This article retraces the steps along this journey, from the curious pharmacological profile of 8‑bromo‑cADPR to the discovery of the cell-wide web, a diverse network of cytoplasmic nanocourses demarcated by S/ER nanojunctions, which direct site-specific calcium flux and may thus coordinate the full panoply of cellular processes.
“…[87][88][89] Several studies revealed that CP, especially S100A9, modulates proliferation of tumour, epithelial and smooth muscle cells, while CP concentrations may differ significantly. [90][91][92][93] CP-induced proliferation was shown to be mediated via RAGE ligation and NF-кB activation in tumour cells, linking inflammation with tumorigenesis. 91 S100A9 may also bind to TLR4 to promote MAPK signalling and monocytic cell differentiation.…”
Section: Extracellular Biological Functions Of Cpmentioning
The incidence of inflammatory bowel diseases (IBD) emerged with Westernisation of dietary habits worldwide. Crohn’s disease and ulcerative colitis are chronic debilitating conditions that afflict individuals with substantial morbidity and challenge healthcare systems across the globe. Since identification and characterisation of calprotectin (CP) in the 1980s, faecal CP emerged as significantly validated, non-invasive biomarker that allows evaluation of gut inflammation. Faecal CP discriminates between inflammatory and non-inflammatory diseases of the gut and portraits the disease course of human IBD. Recent studies revealed insights into biological functions of the CP subunits S100A8 and S100A9 during orchestration of an inflammatory response at mucosal surfaces across organ systems. In this review, we summarise longitudinal evidence for the evolution of CP from biomarker to rheostat of mucosal inflammation and suggest an algorithm for the interpretation of faecal CP in daily clinical practice. We propose that mechanistic insights into the biological function of CP in the gut and beyond may facilitate interpretation of current assays and guide patient-tailored medical therapy in IBD, a concept warranting controlled clinical trials.
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