Phosphatidylinositol-Glycan Anchors of Membrane Proteins: Potential Precursors of Insulin Mediators

Romero, Guillermo; Luttrell, Louis M.; Rogol, Alan D.; Zeller, Konrad; Hewlett, Erik L.; Larner, Joseph

doi:10.1126/science.3282305

Cited by 201 publications

(91 citation statements)

References 29 publications

(19 reference statements)

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“…The nature of the association of that protein with the membrane, however, remains controversial [21]. It was suggested recently that alkaline phosphatase may be released from intact cells by insulin through the activation of an unidentified cellular protease [22]. We believe that the decrease in membrane-bound 5 '-nucleotidase activity reported in our study is not the exclusive result of proteolysis, since PMSF, a serine protease inhibitor, was present during all incubations.…”

Section: Discussionmentioning

confidence: 38%

Insulin‐induced decrease in 5′‐nucleotidase activity in skeletal muscle membranes

et al. 1988

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Insulin releases inositol phosphoglycansfrom myocytes in culture [(1986) Science 233,967-9721, which display insulinomimetic activity. Because S'nucleotidase is anchored to the membrane through inositol-containing phospholipid glycans, we investigated whether insulin could release the enzyme from the membrane. Membranes prepared from hindquarter muscles of rats perfused with insulin showed a 23% decrease in S-nucleotidase activity. Isolated membranes from muscle exposed to insulin in vitro also showed a small but reproducible decrease (9%) in S-nucleotidase activity relative to unexposed controls. Phospholipase C from Staphylococcus aureus released m of the membrane-bound S-nucleotidase. We propose that insulin may activate an endogenous phospholipase C that cleaves phospholipid-glycan-anchored proteins.

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Section: Discussionmentioning

confidence: 38%

Insulin‐induced decrease in 5′‐nucleotidase activity in skeletal muscle membranes

et al. 1988

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“…Additional support for this conclusion has recently been obtained in Leishmania major where at least two glycoinositol phospholipids, structurally related to the present glycosyl-PtdIns, are located on the cell surface [25]. Moreover, the observation that insulin induces the release of at least two proteins, alkaline phosphatase [26] and lipoprotein lipase [27], which are attached to the cell surface through a glycosylPtdIns anchor, indicate the activation by this hormone of a specific phospholipase(s) C with its active site on the cell surface. Similarly, the glycosyl-PtdIns-anchored receptor FcRIII is also released to the incubation medium upon stimulation of neutrophils with the chemotactic peptide formylmethionyl-leucyl-phenylalanine [28], indicating that receptormediated hydrolysis of Ptdlns-linked molecules might be a common step to a variety of cellular activation processes.…”

Section: Orientation Of a Glycosyl-ptdlns In Different Cellsmentioning

confidence: 54%

Asymmetric distribution of the phosphatidylinositol‐linked phospho‐oligosaccharide that mimics insulin action in the plasma membrane

Varela

Alvarez

Clemente

et al. 1990

European Journal of Biochemistry

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We have investigated the topography of a glycosyl-phosphatidylinositol implicated in insulin action by a combination of two complementary methods : (a) chemical labelling with a non-permeable (isethionyl acetimidate) and a permeable (ethyl acetimidate) probe; and (b) enzymatic modifications with P-galactosidase (EC 3.2.1.23) or phosphatidylinositol-specific phospholipase C (EC 3.1.4.3). Using the first approach the majority of the glycosyl-phosphatidylinositol is found in the outer surface of intact hepatocytes, adipocytes, fibroblasts and lymphocytes, but not in erythrocytes which presented only a 20% of the total labelled glycosyl-phosphatidylinositol to the exterior. Upon insulin addition ( 3 0 nM), about 60% of the total glycosyl-phosphatidylinositol was hydrolysed in both hepatocytes and adipocytes but not in erythrocytes. In agreement with the extracellular localization in hepatocytes and with the proposed role of this glycolipid in insulin action, treatment of rat hepatocytes with fl-galactosidase from Escherichia coli, an enzyme that hydrolyses the oligosaccharide moiety of the glycosylphosphatidylinositol, cleaved 65% of the total glycophospholipid and blocked the effect of insulin (but not of glucagon) on pyruvate kinase (EC 2.7.1.40). Similar treatment with phosphatidylinositol-specific phospholipase C from Bacillus cereus hydrolysed 62% of the total glycosyl-phosphatidylinositol. From the various approaches used it is concluded that the majority of this glycophospholipid is at the outer surface in a variety of insulinsensitive cells. In a variety of cells including murine myocytes BC3H1 [l], H35 hepatoma cells [2], T lymphocytes [3] and rat hepatocytes[4], insulin promotes the phosphodiesteratic hydrolysis of a glycosyl-phosphatidylinositol (glycosyl-PtdIns) and thus releases and increases the intracellular levels of the polar headgroup of this lipid. This polar headgroup, a phosphooligosaccharide containing inositol, glucosamine, galactose and phosphate [I, 2, 5, 61, mimics insulin-directed effects on protein phosphorylation/dephosphorylation [7], as well as a variety of the biological effects of this hormone, including lipolysis [8], lipogenesis [9] and the effects of the hormone on pyruvate kinase, glycogen phosphorylase and cyclic AMP levels [lo]. These studies suggest that this glycosyl-Ptdlns is implicated in insulin action. This glycosyl-PtdIns has features in common with the glycosyl-PtdIns anchor of a number of cell membrane proteins (for recent reviews see [I 1 -131). These similarities include : (a) the observation that the insulin-sensitive glycosyl-PtdIns is hydrolysed by the phosphatidyl-inositol-specific phospholipase C (PtdIns-specific phospholiCorrespondence to I. Varela, Metabolismo, Nutricion y Hormonas, Fundacion Jimenez Diaz and C.S.I.C

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“…Separate classes have been identified (3), one containing D-chiro-inositol (DCI) and galactosamine (4) and a second containing myo-inositol (myo-INS) and glucosamine (1)(2)(3)(4)(5). Generated rapidly from lipid and͞or protein precursors in response to insulin, they have insulin-like effects in vitro and in vivo (1,2,4,6,7). Myo-INS phospho-glycans have been prepared by enzymatic cleavage of protein precursors and chemically synthesized (7)(8)(9).…”

mentioning

confidence: 99%

Inositols prevent and reverse endothelial dysfunction in diabetic rat and rabbit vasculature metabolically and by scavenging superoxide

Nascimento

Lessa

Kerntopf

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

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Endothelial dysfunction (ED) is an early feature of cardiovascular risk and diabetes. Hyperglycemia and hyperlipidemia are causative factors. Excessive endothelial mitochondrial superoxide (ROS) production with hyperglycemia and hyperlipidemia is a key mechanism. Inositol components of an insulin inositol glycan mediator, D-chiro-inositol (DCI) and 3-O-methyl DCI (pinitol), decrease hyperglycemia and hyperlipidemia. We tested whether these, myoinositol and dibutyryl DCI (db-DCI), would prevent or reverse ED in diabetic rats and rabbits. Oral inositols reduced hyperglycemia and hypertriglyceridemia with different potencies and prevented ED in rat aortic rings and mesenteric beds. Inositols added in vitro to five diabetic tissues reversed ED. Relaxation by Ach, NO, and electrical field stimulation was potentiated by inositols in vitro in rabbit penile corpus cavernosa. Inositols in vitro restored impaired contraction by the eNOS inhibitor L-NAME and increased NO effectiveness. DCI and db-DCI decreased elevated ROS in endothelial cells in high glucose and db-DCI reduced PKC activation, hexosamine pathway activity, and advanced glycation end products to basal levels. Xanthine͞xanthine oxidase generated superoxide was reduced by superoxide dismutase or inositols, with db-DCI efficacious in a mechanism requiring chelated Fe 3؉ . Histochemical examination of rat aortic rings for protein SNO demonstrated a decrease in diabetic rings with restoration by inositols. In summary, inositols prevented and reversed ED in rat and rabbit vessels, reduced elevated ROS in endothelial cells, potentiated nitrergic or vasculo-myogenic relaxations, and preserved NO signaling. These effects are related to their metabolic actions, direct superoxide scavenging, and enhancing and protecting NO signaling. Of the inositols tested, db-DCI was most effective.I nositol phosphoglycans (IPGs) are potentially important putative intracellular mediators of insulin action (1, 2). Separate classes have been identified (3), one containing D-chiro-inositol (DCI) and galactosamine (4) and a second containing myo-inositol (myo-INS) and glucosamine (1-5). Generated rapidly from lipid and͞or protein precursors in response to insulin, they have insulin-like effects in vitro and in vivo (1, 2, 4, 6, 7). Myo-INS phospho-glycans have been prepared by enzymatic cleavage of protein precursors and chemically synthesized (7-9). They have dose-dependent insulinlike effects on isolated adipocytes, cardiomyocytes, and diaphragms including increased glucose transport (7-9). One DCI containing IPG has been isolated from liver, and its structure has been determined and chemically synthesized (10). It is active in vivo; lowering elevated blood glucose when administered intravenously to diabetic rats (10-12). In vitro, it enhances insulin to stimulate [ 14 C]glucose incorporation into glycogen in H4IIE hepatoma cells (10). It activates pyruvate dehydrogenase (PDH) phosphatase (10), phosphoprotein phosphatase PP2C directly (13), and PP1 indirectly (4,14). Both PDH and glyco...

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Phosphatidylinositol-Glycan Anchors of Membrane Proteins: Potential Precursors of Insulin Mediators

Cited by 201 publications

References 29 publications

Insulin‐induced decrease in 5′‐nucleotidase activity in skeletal muscle membranes

Insulin‐induced decrease in 5′‐nucleotidase activity in skeletal muscle membranes

Asymmetric distribution of the phosphatidylinositol‐linked phospho‐oligosaccharide that mimics insulin action in the plasma membrane

Inositols prevent and reverse endothelial dysfunction in diabetic rat and rabbit vasculature metabolically and by scavenging superoxide

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