Polyamines Inhibit Lipopolysaccharide-Induced Nitric Oxide Synthase Activity in Rat Liver Cytosol

Blachier, François; Mignon, Alexandre; Soubrane, Olivier

doi:10.1006/niox.1997.0127

Cited by 25 publications

(10 citation statements)

References 32 publications

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“…The reason why some GlcNH 3 ϩ residues remained in some, presumably undegraded HS chains of the small glypican glycoform when spermine uptake occurred could be because of a negative feedback mechanism, whereby increased spermine uptake inhibits nitrite formation and, thus, also HS degradation (Scheme 4). It is known that polyamines in general and spermine in particular inhibit NO synthase (30,31), thereby reducing the formation of NO, the precursor of nitrite (32). The present results suggest a functional interplay between glypican recycling, NO/nitrite generation, HS degradation, and polyamine uptake (Scheme 4).…”

Section: Discussionsupporting

confidence: 54%

Modulations of Glypican-1 Heparan Sulfate Structure by Inhibition of Endogenous Polyamine Synthesis

Ding

Sandgren

Mani

et al. 2001

Journal of Biological Chemistry

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Proc. Natl. Acad. Sci. U. S. A., in press). Here, we have analyzed the effect of polyamine deprivation on the structure and polyamine affinity of the heparan sulfate chains in various glypican-1 glycoforms synthesized by a transformed cell line (ECV 304). Heparan sulfate chains of glypican-1 were either cleaved with heparanase at sites embracing the highly modified regions or with nitrite at N-unsubstituted glucosamine residues. The products were separated and further degraded by heparin lyase to identify sulfated iduronic acid. Polyamine affinity was assessed by chromatography on agarose substituted with the polyamine spermine. In heparan sulfate made by cells with undisturbed endogenous polyamine synthesis, free amino groups were restricted to the unmodified, unsulfated segments, especially near the core protein. Spermine high affinity binding sites were located to the modified and highly sulfated segments that were released by heparanase. In cells with up-regulated polyamine uptake, heparan sulfate contained an increased number of clustered N-unsubstituted glucosamines and sulfated iduronic acid residues. This resulted in a greater number of NO/nitrite-sensitive cleavage sites near the potential spermine-binding sites. Endogenous degradation by heparanase and NO-derived nitrite in polyamine-deprived cells generated a separate pool of heparan sulfate oligosaccharides with an exceptionally high affinity for spermine. Spermine uptake in polyamine-deprived cells was reduced when NO/nitrite-generated degradation of heparan sulfate was inhibited. The results suggest a functional interplay between glypican recycling, NO/nitrite-generated heparan sulfate degradation, and polyamine uptake. Proteoglycans (PGs)1 are glycosaminoglycan-substituted proteins that can be found in the extracellular matrix or at the cell surface. Glypican constitutes a family of cell surface-bound PGs where the protein is covalently connected at the C terminus to membrane lipids via a so-called glycosylphosphatidylinositol anchor. The central part of the protein consists of a cysteine-rich globular domain that contains information that ensures a high level of heparan sulfate (HS) glycosaminoglycan substitution at three sites located close to the C terminus (1). So far six different human glypicans with the same overall design have been molecularly cloned (for review, see Ref.2). Biosynthesis of the HS glycan chains proceeds in a stepwise manner. Serine residues in sequences like DDGSGSGSD (glypican-1) are first substituted with xylose and then the common glycosaminoglycan-to-protein linkage region GlcUAGal-Gal-xylose is formed. HS assembly is initiated by a unique ␣-GlcNAc-transferase that adds the first GlcNAc (3). By the alternating addition of GlcUA and GlcNAc, catalyzed by HScopolymerases (4), the extended, linear heparan backbone is formed. A unique step in HS biosynthesis is the regional exchange of N-acetyl for sulfate on glucosamine (4) catalyzed by various isoforms of N-deacetylase/sulfotransferase (NDST). NDST-1, -2, and -4 have an N...

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Section: Discussionsupporting

confidence: 54%

Modulations of Glypican-1 Heparan Sulfate Structure by Inhibition of Endogenous Polyamine Synthesis

Ding

Sandgren

Mani

et al. 2001

Journal of Biological Chemistry

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“…11B), which would be expected to inhibit e-NOS strongly and i-and n-NOS moderately. Spermine inhibits n-NOS at K i = 0.056 mM [23] and possibly i-NOS at K i = 0.5 mM [25], though one report states that it may not inhibit i-NOS [24]. Spermine completely inhibited MMC at a concentration of 0.1 mM (twice the K i value for n-NOS and much lower than the K i for i-NOS), especially in the mdx proximal colon segment (Fig.…”

Section: Discussionmentioning

confidence: 91%

“…Both L-NIO and 1,3-PBIT inhibit e-, i-, and n-NOS at different concentrations [20][21][22]. Spermine, an end-product of polyamine biosynthesis from L-arginine, is a competitive inhibitor of n-and i-NOS [23][24][25]. DPI is an i-NOS inhibitor [26,27].…”

Section: Methodsmentioning

confidence: 99%

The Effect of e-, i-, and n-Nitric Oxide Synthase Inhibition on Colonic Motility in Normal and Muscular Dystrophy (Mdx) Mice

Tameyasu

Ogura

Ogihara

2004

JJP

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(5 µM) reduced the magnitude of local, rhythmic contractions (LC) paced by the interstitial cells of Cajal (ICC), but 1,3-PBIT (50 µM) increased their magnitude. There was no difference in the effect of spermine and 1,3-PBIT on the LC between mdx and control colon. The results suggest an inhibition of MMC by high concentrations of e-, i-, and n-NOS inhibitors, modulation of ICC activity by e-NOS, and greater susceptibility of MMC to n-NOS inhibition in the mdx proximal than in the control colon, which is very likely because of a deficit in n-NOS in the mdx smooth muscle affecting the MMC pacemaker. A deficit in the effect of mdx smooth muscle n-NOS on an MMC pacemaker may be the origin of diarrhea or constipation in human DMD. Japanese Journal of Physiology Vol. 54, [555][556][557][558][559][560][561][562][563][564][565][566] 2004 Abstract: To explore the origin of diarrhea or constipation in human Duchenne muscular dystrophy (DMD), the effect of the inhibition of e-, i-, and n-nitric oxide synthase (NOS) on the motility of proximal and distal segments of colon of muscular dystrophy (mdx) and control mice was studied. The frequency of migrating motor complexes (MMC) was higher in the proximal than in the distal segments in mdx colon (0.56 vs. 0.25 cpm) and in the control colon (0.7 vs. 0.25 cpm), and there was no difference when mdx was compared to control segments. High concentrations of NOS inhibitors, including 1,3-PBIT dihydrobromide (1,3-PBIT) and spermine, inhibited MMC. The dose of spermine required to inhibit MMC was lower for the proximal mdx colon than for the distal mdx or control colon. In the presence of tetrodotoxin, spermine (1 mM) and 1,3-PBIT

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“…As increased NO formation also increases S-nitrosylation of Gpc-1, the latter acquires increased capacity for HS degradation and release of cargo. Conversely, when polyamine levels are high, NO synthesis is inhibited [85,86], S-nitrosylation decreases and so should uptake from the environment. Processing and modulation of Gpc are not confined to the carbohydrate portion.…”

Section: Remaining Issuesmentioning

confidence: 97%

Novel aspects of glypican glycobiology

Fransson

Belting

Cheng

et al. 2004

Cellular and Molecular Life Sciences (CMLS)

112

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Mutations in glypican genes cause dysmorphic and overgrowth syndromes in men and mice, abnormal development in flies and worms, and defective gastrulation in zebrafish and ascidians. All glypican core proteins share a characteristic pattern of 14 conserved cysteine residues. Upstream from the C-terminal membrane anchorage are 3-4 heparan sulfate attachment sites. Cysteines in glypican-1 can become nitrosylated by nitric oxide in a copper-dependent reaction. When glypican-1 is exposed to ascorbate, nitric oxide is released and participates in deaminative cleavage of heparan sulfate at sites where the glucosamines have a free amino group. This process takes place while glypican-1 recycles via a nonclassical, caveolin-1-associated route. Glypicans are involved in growth factor signalling and transport, e.g. of polyamines. Cargo can be unloaded from heparan sulfate by nitric oxide-dependent degradation. How glypican and its degradation products and the cargo exit from the recycling route is an enigma.

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Polyamines Inhibit Lipopolysaccharide-Induced Nitric Oxide Synthase Activity in Rat Liver Cytosol

Cited by 25 publications

References 32 publications

Modulations of Glypican-1 Heparan Sulfate Structure by Inhibition of Endogenous Polyamine Synthesis

Modulations of Glypican-1 Heparan Sulfate Structure by Inhibition of Endogenous Polyamine Synthesis

The Effect of e-, i-, and n-Nitric Oxide Synthase Inhibition on Colonic Motility in Normal and Muscular Dystrophy (Mdx) Mice

Novel aspects of glypican glycobiology

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