UMLS:C0344329 - FACTA Search

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Single channel models of intracellular calcium (Ca(2+)) channels such as the 1,4,5-trisphosphate receptor and ryanodine receptor often assume that Ca(2+)-dependent transitions are mediated by constant background cytosolic [Ca(2+)]. This assumption neglects the fact that Ca(2+) released by open channels may influence subsequent gating through the processes of Ca(2+)-activation or inactivation. Similarly, the influence of the dynamics of luminal depletion on the stochastic gating of intracellular Ca(2+) channels is often neglected, in spite of the fact that the sarco/endoplasmic reticulum [Ca(2+)] near the luminal face of intracellular Ca(2+) channels influences the driving force for Ca(2+), the rate of Ca(2+) release, and the magnitude and time course of the consequent increase in cytosolic domain [Ca(2+)]. Here we analyze how the steady-state open probability of several minimal Ca(2+)-regulated Ca(2+) channel models depends on the conductance of the channel and the time constants for the relaxation of elevated cytosolic [Ca(2+)] and depleted luminal [Ca(2+)] to the bulk [Ca(2+)] of both compartments. Our approach includes Monte Carlo simulation as well as numerical solution of a system of advection-reaction equations for the multivariate probability density of elevated cytosolic [Ca(2+)] and depleted luminal [Ca(2+)] conditioned on each state of the stochastically gating channel. Both methods are subsequently used to study the role of luminal depletion in the dynamics of Ca(2+) puff/spark termination in release sites composed of Ca(2+) channels that are activated, but not inactivated, by cytosolic Ca(2+). The probability density approach shows that such minimal Ca(2+) release site models may exhibit puff/spark-like dynamics in either of two distinct parameter regimes. In one case, puffs/spark termination is due to the process of stochastic attrition and facilitated by rapid Ca(2+) domain collapse [cf. DeRemigio, H., Smith, G., 2005. The dynamics of stochastic attrition viewed as an absorption time on a terminating Markov chain. Cell Calcium 38, 73-86]. In the second case, puff/spark termination is promoted by the local depletion of luminal Ca(2+).
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PMID:The dynamics of luminal depletion and the stochastic gating of Ca2+-activated Ca2+ channels and release sites. 1728 86

Calcium store depletion activates multiple ion channels, including calcium-selective and nonselective channels. Endothelial cells express TRPC1 and TRPC4 proteins that contribute to a calcium-selective store-operated current, I(SOC). Whereas thapsigargin activates the I(SOC) in pulmonary artery endothelial cells (PAECs), it does not activate I(SOC) in pulmonary microvascular endothelial cells (PMVECs), despite inducing a significant rise in global cytosolic calcium. Endoplasmic reticulum exhibits retrograde distribution in PMVECs when compared with PAECs. We therefore sought to determine whether endoplasmic reticulum-to-plasma membrane coupling represents an important determinant of I(SOC) activation in PAECs and PMVECs. Endoplasmic reticulum organization is controlled by microtubules, because nocodozole induced microtubule disassembly and caused retrograde endoplasmic reticulum collapse in PMVECs. In PMVECs, rolipram treatment produced anterograde endoplasmic reticulum distribution and revealed a thapsigargin-activated I(SOC) that was abolished by nocodozole and taxol. Microtubule motors control organelle distribution along microtubule tracks, with the dynein motor causing retrograde movement and the kinesin motor causing anterograde movement. Dynamitin expression reduces dynein motor function inducing anterograde endoplasmic reticulum transport, which allows for direct activation of I(SOC) by thapsigargin in PMVECs. In contrast, expression of dominant negative kinesin light chain reduces kinesin motor function and induces retrograde endoplasmic reticulum transport; dominant negative kinesin light chain expression prevented the direct activation of I(SOC) by thapsigargin in PAECs. I(SOC) activation is an important step leading to disruption of cell-cell adhesion and increased macromolecular permeability. Thus, microtubule motor function plays an essential role in activating cytosolic calcium transitions through the membrane I(SOC) channel leading to endothelial barrier disruption.
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PMID:Microtubule motors regulate ISOC activation necessary to increase endothelial cell permeability. 1792 Nov 44

COPI recruitment to membranes appears to be essential for the biogenesis of the Golgi and for secretory trafficking. Preventing COPI recruitment by expressing inactive forms of the ADP-ribosylation factor (ARF) or the ARF-activating guanine nucleotide exchange factor GBF1, or by treating cells with brefeldin A (BFA), causes the collapse of the Golgi into the endoplasmic reticulum (ER) and arrests trafficking of soluble and transmembrane proteins at the ER. Here, we assess COPI function in Golgi biogenesis and protein trafficking by preventing COPI recruitment to membranes by removing GBF1. We report that siRNA-mediated depletion of GBF1 causes COPI dispersal but does not lead to collapse of the Golgi. Instead, it causes extensive tubulation of the cis-Golgi. The Golgi-derived tubules target to peripheral ER-Golgi intermediate compartment (ERGIC) sites and create dynamic continuities between the ERGIC and the cis-Golgi compartment. COPI dispersal in GBF1-depleted cells causes dramatic inhibition of the trafficking of transmembrane proteins. Unexpectedly, soluble proteins continue to be secreted from GBF1-depleted cells. Our findings suggest that a secretory pathway capable of trafficking soluble proteins can be maintained in cells in which COPI recruitment is compromised by GBF1 depletion. However, the trafficking of transmembrane proteins through the existing pathway requires GBF1-mediated ARF activation and COPI recruitment.
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PMID:Dissecting the role of the ARF guanine nucleotide exchange factor GBF1 in Golgi biogenesis and protein trafficking. 1795 46

Euplectrus separatae is a gregarious ectoparasitoid that parasitizes Pseudaletia separata during its third to sixth (last) instars. The eggs of the parasitoid are fixed on the integument of the host dorsolaterally with a hard substance like a piling driven into the integument by the female wasp at the time of oviposition. The first instar of the parasitoid, which hatches three days after oviposition is nourished by ingesting the hemolymph of the host, and ecdyses to the second stadium six days after oviposition. Many hemocytes and epidermal cells were found assembled under the piling and places where a parasitoid had attached its mouth, suggesting that the host had repaired the integument destroyed by the parasitoid. Botryoidal tissue, which stained well with hematoxylin, began to develop from four days after oviposition and became gradually larger with development. Botryoidal tissue appears to function as a secretory organ for thread and a storage organ for nutrients. Seven days after oviposition, the parasitoid larvae migrate down from the dorsal surface to the ventral side of the host. Just before descending they ecdyse to the third stadium and kill the host during their migration. If all parasitoid larvae were removed artificially from the host before they migrate, the host did not die. However, removing the parasitoids after they had started to migrate did not prevent the death of the host. Transmission electron microscopic (TEM) observation of salivary glands of a parasitoid larva before migrating revealed that the salivary gland was composed of cells that were rich in rough surfaced endoplasmic reticulum (rough-ER) with many ribosomes and cells that were filled with a lot of vacuoles just before their collapse. After moving from the host body, the parasitoid larvae doubled in weight by ingesting the tissue of the host and then spun a cocoon. Almost all host tissues were consumed for growth of the parasitoid, like an idiobiont parasitoid.
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PMID:Development of a gregarious ectoparasitoid, Euplectrus separatae (Hymenoptera; Hymenoptera: Eulophidae), that parasitizes Pseudaletia separata (Lepidoptera: Noctuidae). 1808 16

Histological and electron microscopic examinations of the kidneys of 8 dogs suffering from fatal, naturally acquired Babesia canis infection and nephropathy are presented. Seven animals were treated with imidocarb dipropionate on average 4.5 days prior to death. Severe anaemia was present only in 2 cases. Degenerative histological changes observed mostly in the proximal convoluted tubules included vacuolar-hydropic degeneration, necrosis and detachment of renal tubular epithelial (RTE) cells from the basement membrane. Necrotic debris occasionally formed acidophilic casts within the tubules. In some cases, necrosis of the whole tubule was observed. Haemoglobin casts in the tubules and haemoglobin droplets in RTE cells seldom appeared. No significant histological changes were seen in the glomeruli. Ultrastructural lesions in RTE cells included nuclear membrane hyperchromatosis, karyopyknosis, karyolysis, swelling or collapse of mitochondria with fragmentation of cristae and vacuolar-hydropic degeneration in the endoplasmic reticulum and microvilli. Nuclear oedema was also observed. Many RTE cells exhibiting necrosis collapsed. Vacuolar-hydropic degeneration and necrosis were also observed in the glomerular and interstitial capillary endothelium. The severe acute tubular necrosis described in this study is probably the result of hypoxic renal injury. Systemic hypotension leading to vasoconstriction in the kidneys might be the most important cause of renal hypoxia in B. canis infections, but anaemia may also contribute to inadequate oxygenation. Imidocarb should be applied with caution in patients with possible renal involvement until further data become available on its potential nephrotoxicity in dogs.
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PMID:Histological and ultrastructural studies of renal lesions in Babesia canis infected dogs treated with imidocarb. 1827 10

In the search for new therapeutic agents for Chagas' disease, we screened extracts obtained from the Brazilian plant Pterodon pubescens found commercially in the medicinal flora market. We investigated the potential trypanocidal effect of the oleaginous ethanolic extract of P. pubescens seeds and its fractions (PF1, PF1.1, PF1.2, and PF1.3) and of geranylgeraniol (GG-OH), the sole component of the hexane fraction (PF1.2). In experiments with bloodstream trypomastigotes of Trypanosoma cruzi, performed at 37 degrees C in culture medium, PF1.2 and GG-OH showed similar potency, while the oleaginous extract from P. pubescens seeds and the other fractions were about three times less active. GG-OH inhibited the proliferation of intracellular amastigotes, at concentrations which do not affect the mammalian host cell. Transmission electron microscopy and flow cytometry analysis indicate the mitochondrion, an organelle that plays a central role in apoptosis, of both epimastigotes and of trypomastigotes as the major target of GG-OH. On the other hand, the ultrastructural images of the endoplasmic reticulum profiles, myelin-like figures, and concentric membranous arrangements inside damaged mitochondrion are suggestive of an autophagic pathway leading to parasite death. Because the different forms of cell death share some morphological features such as mitochondrial collapse, further studies are needed to disclose the trypanocidal action of GG-OH.
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PMID:Anti-Trypanosoma cruzi activity of Pterodon pubescens seed oil: geranylgeraniol as the major bioactive component. 1834 52

We have utilized small interfering RNA (siRNA)-mediated depletion of the beta-COP subunit of COP-I to explore COP-I function in organellar compartmentalization and protein traffic. Reduction in beta-COP levels causes the colocalization of markers for the endoplasmic reticulum (ER)-Golgi intermediate compartment (ERGIC), Golgi, trans-Golgi network (TGN), and recycling endosomes in large, globular compartments. The lack of spatial differentiation of these compartments is not due to a general collapse of all cellular organelles since markers for the early endosomes and lysosomes do not redistribute to the common structures. Anterograde trafficking of the transmembrane cargo vesicular stomatitis virus membrane glycoprotein and of a subset of soluble cargoes is arrested within the common globular compartments. Similarly, recycling traffic of transferrin through the common compartment is perturbed. Furthermore, the trafficking of caveolin-1 (Cav1), a structural protein of caveolae, is arrested within the globular structures. Importantly, Cav1 coprecipitates with the gamma-subunit of COP-I, suggesting that Cav1 is a COP-I cargo. Our findings suggest that COP-I is required for the compartmentalization of the ERGIC, Golgi, TGN, and recycling endosomes and that COP-I plays a novel role in the biosynthetic transport of Cav1.
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PMID:Depletion of beta-COP reveals a role for COP-I in compartmentalization of secretory compartments and in biosynthetic transport of caveolin-1. 1838 91

The new 7-bromoindirubin-3'-oxime (7BIO) compound induces caspase-independent cell death in all cell lines tested to date. Irrespective of the cell line, a 25 microM treatment for 24 h is lethal for the entire cell population. In SH-SY5Y and Jurkat cells, 7BIO (25 microM) was found to collapse the mitochondrial transmembrane potential (DeltaPsi m) at only 2-3 h of treatment. Concomitantly mitochondria swelled, cristae disrupted and, after 9 h, external cell membranes ruptured. In addition, endoplasmic reticulum dilated and, unexpectedly, the acute cytoplasmic destruction yielded isolated nuclei with preserved morphology and DNA integrity. Furthermore, the process was independent of both Bax and Bak, since cell viability and DeltaPsi m decayed indistinguishably in double Bax-/-Bak-/- mouse embryonic fibroblasts (MEFs) and their wild type counterparts. Pharmacological inhibition of the mitochondrial permeability transition pore (MPTP) did not prevent 7BIO-induced DeltaPsi m loss in none of the aforementioned cell lines. Caspase-independent inducers of cell death like AIF (Apoptosis Inducing Factor), cathepsins and calpains were not involved. Only the chemical inhibitors of serine proteases and, particularly, AEBSF afforded a significant protection thus suggesting a process regulated by this type of enzymes. As far as we know, these features are quite unique once taken together. Therefore, we propose 7BIO is triggering a specific type of necrotic cell death. Finally, the cytotoxicity of 7BIO on apoptosis-resistant cells like double Bax-/-Bak-/- MEFs seems of great interest envisaging cancer therapy.
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PMID:7-Bromoindirubin-3'-oxime uncovers a serine protease-mediated paradigm of necrotic cell death. 1848 31

The inositol 1,4,5-trisphosphate receptor/channel (IP(3)R) is a major regulator of intracellular Ca(2+) signaling, and liberates Ca(2+) ions from the endoplasmic reticulum in response to binding at cytosolic sites for both IP(3) and Ca(2+). Although the steady-state gating properties of the IP(3)R have been extensively studied and modeled under conditions of fixed [IP(3)] and [Ca(2+)], little is known about how Ca(2+) flux through a channel may modulate the gating of that same channel by feedback onto activating and inhibitory Ca(2+) binding sites. We thus simulated the dynamics of Ca(2+) self-feedback on monomeric and tetrameric IP(3)R models. A major conclusion is that self-activation depends crucially on stationary cytosolic Ca(2+) buffers that slow the collapse of the local [Ca(2+)] microdomain after closure. This promotes burst-like reopenings by the rebinding of Ca(2+) to the activating site; whereas inhibitory actions are substantially independent of stationary buffers but are strongly dependent on the location of the inhibitory Ca(2+) binding site on the IP(3)R in relation to the channel pore.
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PMID:Modeling Ca2+ feedback on a single inositol 1,4,5-trisphosphate receptor and its modulation by Ca2+ buffers. 1864 Oct 77

Protein disulfide isomerase (PDI) oxidizes, reduces, and isomerizes disulfide bonds, modulates redox responses, and chaperones proteins. The Arabidopsis thaliana genome contains 12 PDI genes, but little is known about their subcellular locations and functions. We demonstrate that PDI5 is expressed in endothelial cells about to undergo programmed cell death (PCD) in developing seeds. PDI5 interacts with three different Cys proteases in yeast two-hybrid screens. One of these traffics together with PDI5 from the endoplasmic reticulum through the Golgi to vacuoles, and its recombinant form is functionally inhibited by recombinant PDI5 in vitro. Peak PDI5 expression in endothelial cells precedes PCD, whereas decreasing PDI5 levels coincide with the onset of PCD-related cellular changes, such as enlargement and subsequent collapse of protein storage vacuoles, lytic vacuole shrinkage and degradation, and nuclear condensation and fragmentation. Loss of PDI5 function leads to premature initiation of PCD during embryogenesis and to fewer, often nonviable, seeds. We propose that PDI5 is required for proper seed development and regulates the timing of PCD by chaperoning and inhibiting Cys proteases during their trafficking to vacuoles before PCD of the endothelial cells. During this transitional phase of endothelial cell development, the protein storage vacuoles become the de facto lytic vacuoles that mediate PCD.
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PMID:Arabidopsis protein disulfide isomerase-5 inhibits cysteine proteases during trafficking to vacuoles before programmed cell death of the endothelium in developing seeds. 1867 77

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