Recent studies have shown that orally supplied nitrates, which substantially exist in our daily diets, are reduced into nitrites and become significant sources of nitric oxide (NO) especially in hypoxic tissues. However, physiological significance of nitrites in normal tissues has not been elucidated though our serum concentrations of nitrites reach as high as micromolar levels. We investigated effects of nitrite on endothelial NO synthase (eNOS) using human glomerular endothelial cells to reveal potential glomerular-protective actions of nitrites with its underlying molecular mechanism. Here we demonstrate that nitrite stimulation evokes eNOS activation which is dependent on 5′AMP-activated protein kinase (AMPK) activation in accordance with ATP reduction. Thus, nitrites should facilitate AMPK-eNOS pathway in an energy level-dependent manner in endothelial cells. The activation of AMPK-eNOS signals is suggested to be involved in vascular and renal protective effects of nitrites and nitrates. Nitrites may harbor beneficial effects on metabolic regulations as AMPK activators.Key words nitrite; 5′AMP-activated protein kinase; endothelial nitric oxide synthase; human glomerular endothelial cell (HGEC); nitrate Nitric oxide (NO) is an important signaling molecule involved in many physiological processes. Above all, NO is a dominant vasodilator released from endothelial cells and identified as the nature of endothelium-derived relaxant factor so called, which regulates blood pressures.1) In addition, NO prevents endothelial apoptosis, platelet aggregation and has tissue-protective actions against such proinflammatory and proatherogenic stimulations.2-4) NO is produced from arginine by three distinct isoforms of nitric oxide synthase (NOS). In uninjured endothelial cells, endothelial NOS (eNOS) dominantly catabolizes the NO production. Therefore, appropriate regulation of eNOS activity is quite important to keep vessels and tissues in good conditions. Disruption of endothelial NO synthesis has been reported in such diseases as hypertension, diabetes and hyperlipidemia in accordance. 5-8)The half-life of NO in blood is just in seconds and metabolized into inert nitrate via nitrite. In addition, our daily diets, especially vegetables, ordinarily contain considerable amounts of nitrate and nitrite, and significant concentrations of them distributes throughout our bodies. An analysis using capillary electrophoresis revealed the concentrations of nitrite and nitrate in normal human serum are around 6.6 and 34 µM, respectively. 9)Exogenous NO sources constitute a powerful way to supplement NO when the body cannot generate it enough for normal biological functions. Recent studies have established the notion of nitrate-nitrite-NO pathway (reviewed in 10,11) ). In brief, dietary and salivary glands-secreted nitrate is reduced into nitrite by bacteria in oral cavity. The nitrite is converted into nitrogen oxides including NO in the stomach or other acidic environments. The resultant nitrate in the plasma is taken up and re-secr...
Synaptobrevin, also called vesicle-associated membrane protein (VAMP), is a component of the plasma membrane N-methylmaleimide-sensitive factor attachment protein receptor (SNARE) complex, which plays a key role in intracellular membrane fusion. Previous studies have revealed that, similar to synaptobrevin in other organisms, the fission yeast synaptobrevin ortholog Syb1 associates with post-Golgi secretory vesicles and is essential for cytokinesis and cell elongation. Here, we report that Syb1 has a role in sporulation. After nitrogen starvation, green fluorescent protein (GFP)-Syb1 is found in intracellular dots. As meiosis proceeds, GFP-Syb1 accumulates around the nucleus and then localizes at the forespore membrane (FSM). We isolated a syb-S1 mutant, which exhibits a defect in sporulation. In syb1-S1 mutants, the FSM begins to form but fails to develop a normal morphology. Electron microscopy shows that an abnormal spore wall is often formed in syb1-S1 mutant spores. Although most syb1-S1 mutant spores are germinated, they are less tolerant to ethanol than wild-type spores. The syb1-S1 allele carries a missense mutation, resulting in replacement of a conserved cysteine residue adjacent to the transmembrane domain, which reduces the stability and abundance of the Syb1 protein. Taken together, these results indicate that Syb1 plays an important role in both FSM assembly and spore wall formation. Members of the soluble N-methylmaleimide-sensitive factor attachment protein receptor (SNARE) family contribute to transport specificity by regulating interactions between membrane vesicles and their appropriate target membranes (1). SNARE proteins exist as complementary sets of v-SNAREs, found on vesicle membranes, and t-SNAREs, found on target membranes. Recent classification, however, takes into account the structural features of SNARE proteins, subdividing them into RSNAREs and Q-SNAREs (2).There are approximately 40 SNAREs in an animal cell, and each associates with a particular organelle in the biosyntheticsecretory or endocytic pathway (3). A v-SNARE is a single polypeptide chain, whereas a t-SNARE complex is composed of two or three proteins. The v-SNAREs and t-SNAREs have characteristic helical domains, and when a v-SNARE interacts with a t-SNARE, the helical domains of one wrap around the helical domains of the other to form a stable four-helix bundle. The resulting trans-SNARE complex locks the two membranes together.SNAREs have been well characterized in neurons, where they mediate the docking and fusion of synaptic vesicles at the nerve terminal's plasma membrane (PM) during the process of neurotransmitter release. The SNARE complex responsible for docking synaptic vesicles at the PM of nerve terminals consists of three proteins. The transmembrane proteins v-SNARE synaptobrevin (also called vesicle-associated membrane protein [VAMP]) and t-SNARE syntaxin each contribute one ␣-helix to the complex (4, 5), whereas the peripheral membrane protein t-SNARE SNAP-25 contributes two ␣-helices to the four-helix bun...
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