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 28,634 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The fluorescent calcium probe, Fluo-3, AM was used to measure the intracellular calcium concentration in red blood cells (RBCs) of the teiid lizards Ameiva ameiva and Tupinambis merianae. The cytosolic [Ca2+] is maintained around 20 nM and the cells contain membrane-bound Ca2+ pools. One pool appears to be identifiable with the endoplasmic reticulum (ER) inasmuch as addition of the sarco-endoplasmic reticulum Ca2+ ATPase, SERCA, inhibitor thapsigargin induces an increase in cytosolic [Ca2+ both in the presence and in the absence of extracellular Ca2+. In addition to the ER, an acidic compartment appears to be involved in Ca2+ storage, as collapse of intracellular pHgradients by monensin, a Na+ -H+ exchanger, and nigericin, a K+ -H+ exchanger, induce the release of Ca2+ from internal pools. A vacuolar H+ pump, sensitive to NBD-Cl and bafilomycin appears to be necessary to load the acidic Ca2+ pools. Finally, the purinergic agonist ATP triggers a rapid and transient increase of [Ca2+]c in the cells from both lizard species, mostly by mobilization of the cation from internal stores.
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PMID:Signal transduction in red blood cells of the lizards Ameiva ameiva and Tupinambis merianae (Squamata, Teiidae). 1135 9

Active trafficking from the Golgi apparatus is involved in acrosome formation, both by delivering acrosomal contents to the nascent secretory vesicle and by controlling organelle growth and shaping. During murine spermiogenesis, Golgi antigens (giantin, beta-COP, golgin 97, mannosidase II) are detected in the acrosome until the late cap-phase spermatids, but are not found in testicular spermatozoa (maturation-phase spermatids). This suggests that Golgi-acrosome flow may be relatively unselective, with Golgi residents retrieved before spermiation is complete. Treatment of spermatogenic cells with brefeldin A, a drug that causes the Golgi apparatus to collapse into the endoplasmic reticulum, disrupted the Golgi in both pachytene spermatocytes and round spermatids. However, this treatment did not affect the acrosomal granule, and some beta-COP labeling on the acrosome of elongating spermatids was maintained. Additionally, N-ethylmaleimide sensitive factor, soluble NSF attachment proteins, and homologues of the t-SNARE syntaxin and of the v-SNARE VAMP/synaptobrevin, as well as members of the rab family of small GTPases, are associated with the acrosome (but not the acrosomal granule) in round and elongated spermatids. This suggests that rab proteins and the SNARE machinery for membrane recognition/docking/fusion may be involved in trafficking during mammalian acrosome biogenesis.
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PMID:Membrane trafficking machinery components associated with the mammalian acrosome during spermiogenesis. 1141 37

Prosomatostatin, the precursor of the hormone somatostatin, harbors an N-glycosylation site in its prodomain that has never been shown to be modified by the N-oligosaccharyl transferase (OST) of the endoplasmic reticulum (ER). The addition of Brefeldin A (BFA) to prosomatostatin transfected AtT20 cells leads to a quantitative glycosylation of the prohormone. Upon removal of the BFA the glycosylated hormone precursor is not deglycosylated, and is secreted after maturation of its oligosaccharide chain in the late secretory pathway. In addition, a significant proportion of the glycosylated hormone precursor remains in the cell. Since BFA is known to induce an effective collapse of the Golgi complex into the ER, the hypothesis that a prolonged exposure to the ER glycosylation machinery is responsible for the glycosylation was tested. No N-glycosylation was detected using a coupled in vitro transcription-translation system in the presence of canine pancreatic microsomes, indicating that rapid transit through the ER does not explain the lack of glycosylation observed in vivo in the absence of BFA. These observations show that co-translational glycosylation by OST becomes possible due to a still unidentified modification in the luminal environment brought about by the coalescence of the Golgi into the ER caused by BFA.
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PMID:Brefeldin A-induced prosomatostatin N-glycosylation in AtT20 cells. 1217 26

Both wild-type (S21-WT) and hrpD- (S21-533) strains of Pseudomonas syringae pv phaseolicola induced the formation of large paramural papillae in lettuce (Lactuca sativa) mesophyll cells adjacent to bacterial colonies. Localized alterations to the plant cell wall included deposition of hydroxyproline-rich glycoproteins, phe-nolics, and callose, and were associated with proliferation of the endoplasmic reticulum and multivesicular bodies. Tissue collapse during the hypersensitive reaction caused by S21-WT was associated with electrolyte leakage and rapid accumulation of the phy-toalexin lettucenin A, both of which followed membrane damage indicated by the failure of mesophyll cells to plasmolyze. A few cells lost the ability to plasmolyze after inoculation with S21-533, and low levels of lettucenin A were recorded, but neither leakage of electrolytes nor tissue collapse were detected. Dysfunction of the plasma membrane in cells adjacent to colonies of S21-WT led to extensive vacuolation of the cytoplasm, organelle disruption, and cytoplasmic collapse[mdash]changes unlike those occurring in cells undergoing apoptosis. Strain S21-533 remained viable within symptomless tissue, whereas cells of S21-WT were killed as a consequence of the hypersensitive reaction. Our observations emphasize the subtle coordination of the plant's response occurring at the subcellular level.
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PMID:Hrp Mutant of Pseudomonas syringae pv phaseolicola Induces Cell Wall Alterations but Not Membrane Damage Leading to the Hypersensitive Reaction in Lettuce. 1222 88

The active neurotoxin of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), 1-methyl-4-phenylpyridinium (MPP+), exerts its lethal effect by inhibiting Complex I of the electron transport chain (ETC). MPP+ shuts down aerobic oxidative phosphorylation and ETC-mediated ATP synthesis. The present investigation examines anaerobic survival during MPP+ toxicity in murine neuroblastoma cells Neuro 2-A (N2-A). MPP+ addition to the cells resulted in a reduction in cell viability, mitochondrial O(2) consumption (MOC) and ATP concentration in a dose-dependent manner. However, the addition of 10 mM of D-(+)-glucose prevented MPP+ toxicity, attenuated the loss of ATP, but did not reverse the complete inhibition of MOC, indicating substrate level phosphorylation and explicit anaerobic survival. Glucose addition prevented MPP+-mediated drop in DeltaPsim, endoplasmic reticulum and intracellular organelle membrane potential tantamount to an increase of cell viability. Secondly, we examined the metabolic regulation of pyruvate dehydrogenase (PDH) and carnitine palmitoyl transferase (CPT) activities during glucose rescue. These enzymes exert control over acetyl CoA reservoirs in the mitochondria during aerobic metabolism. DL-6,8-Thioctic acid (PDH prosthetic group) and insulin slightly augmented metabolic rate, resulting in enhanced vulnerability to MPP+ in a glucose-limited environment. Additional glucose prevented these effects. Amiodarone (CPT inhibitor) and glucagon did not hamper or potentiate glucose rescue against MPP+. These data support strict anaerobic glucose utilization in the presence of toxic levels of MPP+. Moreover, the findings indicate that MPP+ exerts two distinct modes of toxicity (fast and slow death). With MPP+ (<1 mM), anaerobic glycolysis is operational, and toxicity is strictly dependent upon glucose depletion. MPP+ (1-10 mM) initiated acute metabolic collapse, with failure to sustain or switch to anaerobic glycolysis. In conclusion, overcoming energy failure against MPP+ may involve targeting rate-limiting controls over anaerobic energy pathways.
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PMID:D-(+)-glucose rescue against 1-methyl-4-phenylpyridinium toxicity through anaerobic glycolysis in neuroblastoma cells. 1254 55

Cellular Ca2+ signals are crucial in the control of most physiological processes, cell injury and programmed cell death through the regulation of a number of Ca2+-dependent enzymes such as phospholipases, proteases, and nucleases. Mitochondria along with the endoplasmic reticulum play pivotal roles in regulating intracellular Ca2+ content. Mitochondria are endowed with multiple Ca2+ transport mechanisms by which they take up and release Ca2+ across their inner membrane. During cellular Ca2+ overload, mitochondria take up cytosolic Ca2+, which in turn induces opening of permeability transition pores and disrupts the mitochondrial membrane potential (deltapsim). The collapse of deltapsim along with the release of cytochrome c from mitochondria is followed by the activation of caspases, nuclear fragmentation and cell death. Members of the Bcl-2 family are a group of proteins that play important roles in apoptosis regulation. Members of this family appear to differentially regulate intracellular Ca2+ level. Translocation of Bax, an apoptotic signaling protein, from the cytosol to the mitochondrial membrane is another step in this apoptosis signaling pathway.
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PMID:Mitochondria, calcium and pro-apoptotic proteins as mediators in cell death signaling. 1256 19

A phenotypic screen was used to search for drug-like molecules that can interfere with specific steps in membrane traffic. 2-(4-Fluorobenzoylamino)-benzoic acid methyl ester (Exo1), identified in this screen, induces a rapid collapse of the Golgi to the endoplasmic reticulum, thus acutely inhibiting the traffic emanating from the endoplasmic reticulum. Like Brefeldin A (BFA), Exo1 induces the rapid release of ADP-ribosylation factor (ARF) 1 from Golgi membranes but has less effect on the organization of the trans-Golgi network. Our data indicate that Exo1 acts by a different mechanism from BFA. Unlike BFA, Exo1 does not induce the ADP-ribosylation of CtBP/Bars50 and does not interfere with the activity of guanine nucleotide exchange factors specific for Golgi-based ARFs. Thus, Exo1 allows the fatty acid exchange activity of Bars50 to be distinguished from ARF1 activity in the control of Golgi tubulation.
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PMID:Exo1: a new chemical inhibitor of the exocytic pathway. 1273 86

Nogo-A is a potent neurite growth inhibitor in vitro and plays a role both in the restriction of axonal regeneration after injury and in structural plasticity in the CNS of higher vertebrates. The regions that mediate inhibition and the topology of the molecule in the plasma membrane have to be defined. Here we demonstrate the presence of three different active sites: (1) an N-terminal region involved in the inhibition of fibroblast spreading, (2) a stretch encoded by the Nogo-A-specific exon that restricts neurite outgrowth and cell spreading and induces growth cone collapse, and (3) a C-terminal region (Nogo-66) with growth cone collapsing function. We show that Nogo-A-specific active fragments bind to the cell surface of responsive cells and to rat brain cortical membranes, suggesting the existence of specific binding partners or receptors. Several antibodies against different epitopes on the Nogo-A-specific part of the protein as well as antisera against the 66 aa loop in the C-terminus stain the cell surface of living cultured oligodendrocytes. Nogo-A is also labeled by nonmembrane-permeable biotin derivatives applied to living oligodendrocyte cultures. Immunofluorescent staining of intracellular, endoplasmic reticulum-associated Nogo-A in cells after selective permeabilization of the plasma membrane reveals that the epitopes of Nogo-A, shown to be accessible at the cell surface, are exposed to the cytoplasm. This suggests that Nogo-A could have a second membrane topology. The two proposed topological variants may have different intracellular as well as extracellular functions.
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PMID:Nogo-A inhibits neurite outgrowth and cell spreading with three discrete regions. 1284 38

The disease complex medullary cystic disease/familial juvenile hyperuricemic nephropathy (MCKD/FJHN) is characterized by alteration of urinary concentrating ability, frequent hyperuricemia, tubulo-interstitial fibrosis, cysts at the cortico-medullary junction and renal failure. MCKD/FJHN is caused by mutations of the gene encoding uromodulin, the most abundant protein in urine. Here, we describe new missense mutations in three families with MCKD/FJHN and demonstrate allelism with a glomerulocystic kidney disease (GCKD) variant, showing association of cyst dilatation and collapse of glomeruli with some clinical features similar to MCKD/FJHN as hyperuricemia and impairment of urine concentrating ability. Furthermore, we provide the first functional characterization of uromodulin mutations. The four newly identified mutants were characterized by immunofluorescence and FACS analysis on transfected cells. These experiments showed that all uromodulin mutations cause a delay in protein export to the plasma membrane due to a longer retention time in the endoplasmic reticulum. Immunohistochemistry on GCKD and MCKD/FJHN kidney biopsies revealed dense intracellular accumulation of uromodulin in tubular epithelia of the thick ascending limb of Henle's loop. Electron microscopy demonstrated accumulation of dense fibrillar material within the endoplasmic reticulum. Consistently, patient urines show a severe reduction of excreted uromodulin. The maturation impairment is consistent with the clinical findings and suggests a pathogenetic mechanism leading to these kidney diseases.
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PMID:Allelism of MCKD, FJHN and GCKD caused by impairment of uromodulin export dynamics. 1457 Jul 9

Intracellular transport and egress of alphaherpesviruses require the coordinate function of multiple proteins and glycoproteins. Recently, we showed that gK is expressed on infected cell surfaces and that gK cell-surface expression required the presence of the UL20 protein [J. Virol. 77 (2003), 499]. Overexpression of gK by gK-transformed cells blocked transport of enveloped virions from perinuclear spaces and inhibited virus-induced cell fusion caused by gK syncytial mutants [J. Virol. 69 (1995), 5401]. Therefore, we investigated whether altered synthesis and transport of gK was responsible for the observed gK-mediated interference phenomena. HSV-1 infection of the gK-transformed cell line Vero (gK9) caused a profound entrapment of gK in the endoplasmic reticulum and total inhibition of gK cell surface expression. In addition, gK drastically inhibited intracellular transport and maturation of gD and caused substantial defects in Golgi-dependent glycosylation of gB. Visualization of intracellular organelles via confocal microscopy revealed a profound collapse of the Golgi apparatus into the endoplasmic reticulum. These results were analogous to those observed in the presence of brefeldin A, a known Golgi disruptor. Therefore, virion entrapment within perinuclear spaces and inhibition of glycoprotein transport are due to gK-mediated collapse of the Golgi apparatus.
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PMID:Overexpression of gK in gK-transformed cells collapses the Golgi apparatus into the endoplasmic reticulum inhibiting virion egress, glycoprotein transport, and virus-induced cell fusion. 1469 63


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