Biosynthesis of cyclic AMP antagonist in hepatocytes from rats after adrenalin‐ or insulin‐stimulation

Wasner, H.K.

doi:10.1016/0014-5793(81)80519-4

Cited by 31 publications

(14 citation statements)

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“…Existence, purification and chemical structure of the endogenous, functional cyclic AMP antagonist cyclic PIP have been reported (Wasner, 1981;Wasner et al, 1992;. It is a prostaglandylinositol cyclic phosphate, which activates serine/threonine protein phosphatases and inhibits protein kinases A (Wasner, 1975).…”

Section: Introductionmentioning

confidence: 99%

Two Different Mechanisms for Activation of Cyclic PIP Synthase: by a G Protein or by Protein Tyrosine Phosphorylation

Wasner¹,

Gebel²,

Hucken³

et al. 2000

Biological Chemistry

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The biosynthesis of the functional, endogenous cyclic AMP antagonist, prostaglandylinositol cyclic phosphate (cyclic PIP) is performed by the plasma membrane-bound enzyme cyclic PIP synthase, which combines prostaglandin E (PGE) and activated inositol phosphate (n-IP) to cyclic PIP. The Km values of the enzyme for the substrates PGE and n-IP are in the micromolar range. The plasma membrane-bound synthase is activated by fluoride, by the stable GTP analog GMP-PNP, by protamine or biguanide, by noradrenaline, and by insulin. The activation by protamine or biguanide and fluoride (10 mM) is additive, which may indicate the presence of two different types of enzyme, comparable to phospholipase Cbeta and phospholipase Cgamma. Plasma membrane-bound cyclic PIP synthase is inhibited by the protein tyrosine kinase inhibitor tyrphostin B46 with an IC50 of 1.7 microM. However, the solubilized and gel-filtrated enzyme is no longer inhibited by tyrphostin, indicating that the activity of cyclic PIP synthase is connected with the activity of a membrane-bound protein tyrosine kinase. Cyclic PIP synthase activity of freshly prepared plasma membranes is unstable. Upon freezing and rethawing of liver plasma membranes, this instability is increased about 2-fold. Protein tyrosine phosphatase inhibitors [vanadate, fluoride (50-100 mM)] stabilize the enzyme activity, but protease inhibitors do not, indicating that inactivation of the enzyme is connected with protein tyrosine dephosphorylation. Cyclic PIP synthase is present in all tissues tested, like brain, heart, intestine, kidney, liver, lung, skeletal muscle, spleen, and testis. Apart from liver, cyclic PIP synthase activity in most tissues is rather low, but it can be increased up to 5-fold when protein tyrosine phosphatase inhibitors like vanadate are present in the homogenization buffer. Preincubation of cyclic PIP synthase of liver plasma membranes with the tyrosine kinase src kinase causes a 2-fold increase of cyclic PIP synthase activity, though this is certainly not the physiological role played by src kinase in intact cells. The data indicate that cyclic PIP synthase can be activated by two separate mechanisms: by a G protein or by protein tyrosine phosphorylation.

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Section: Introductionmentioning

confidence: 99%

Two Different Mechanisms for Activation of Cyclic PIP Synthase: by a G Protein or by Protein Tyrosine Phosphorylation

Wasner¹,

Gebel²,

Hucken³

et al. 2000

Biological Chemistry

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“…It has been shown in rat liver that insulin stimulation increases cPIP synthesis rapidly (within minutes) [94]. cPIP synthase is dephosphorylated rapidly and cPIP synthase activity appears to be the result of a dynamic equilibrium state of continuous phosphorylation/dephosphorylation [31].…”

Section: Resultsmentioning

confidence: 99%

Prostaglandylinositol cyclic phosphate (cPIP): a novel second messenger of insulin action. Comparative analysis of two kinds of ‘insulin mediators’

Shashkin

Wasner

Ortmeyer

et al. 2001

Diabetes Metabolism Res

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Insulin induces a broad spectrum of effects over a wide time interval. It also stimulates the phosphorylation of some cellular proteins, while decreasing the state of phosphorylation of others. These observations indicate the presence of different, but not necessarily mutually exclusive, pathways of insulin action. One well-known pathway represents a phosphorylation cascade initiated by the tyrosine kinase activity of the insulin receptor followed by involvement of different MAP-kinases. Another pathway suggests the existence of low molecular weight insulin mediators whose synthesis and/or release is initiated by insulin. Comparable analysis of two kinds of insulin mediators, namely inositolphosphoglycans and prostaglandylinositol cyclic phosphate (cPIP), has been carried out. It has been shown that the expression of a number of enzymes, such as phospholipase A(2), phospholipase C, cyclo-oxygenase and IRS-1-like enzyme, could regulate the biosynthesis of cPIP in both normal and diabetes-related conditions. Data on the activity of a key enzyme of cPIP biosynthesis termed cPIP synthase (IRS-1-like enzyme) in various monkey tissues before and twice during an euglycemic hyperinsulinemic clamp have been presented. It has been concluded that in vivo insulin increases cPIP synthase activity in both liver and subcutaneous adipose tissue of lean normal monkeys. It has been also suggested that abnormal production of cPIP could be related to several pathologies including glucocorticoid-induced insulin resistance and diabetic embryopathy. Further studies on cPIP and other types of insulin mediators are necessary to aid our understanding of insulin action.

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“…The amount of extractable PI is close to 10-fold higher than the amount of isolated cyclic PIP (Wasner et al, 1992(Wasner et al, , 1993, indicating that in rat liver degradation of cyclic PIP is nearly as rapid as its synthesis. The time course of cyclic PIP synthesis peaks within 3 min after hormonal stimulation and cyclic PIP levels decrease to nearly basal levels within 10 min thereafter (Wasner, 1981), this may also indicate that degradation of cyclic PIP is rapid. Therefore the degrading enzyme or enzymes of cyclic PIP had to be systematically studied prior to the search for inhibitors.…”

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confidence: 97%

“…The functional cyclic AMP antagonist, cyclic PIP, first isolated from hepatocytes (Wasner, 1981) has been detected in all rat organs so far tested (Wasner et al, 1993). The cAMP antagonist is also present in the yeast Saccharomyces cerevisiae (Wasner and Salge, 1987) and in the slime mould Dictyostelium discoideum (Kaiser et al, 1998).…”

mentioning

confidence: 99%

“…The cAMP antagonist is also present in the yeast Saccharomyces cerevisiae (Wasner and Salge, 1987) and in the slime mould Dictyostelium discoideum (Kaiser et al, 1998). Hormones like insulin and noradrenaline (␣-adrenergic action) stimulate the synthesis of cyclic PIP (Wasner, 1981;Wasner et al, 1993), whose regulatory properties are activation of protein serine/threonine phosphatases and inhibition of protein kinase A (Wasner, 1975). Cyclic PIP is composed of prostaglandin E (PGE) and inositol phosphate, i.e.…”

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confidence: 99%

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Degradation of the Cyclic AMP Antagonist Prostaglandylinositol Cyclic Phosphate (Cyclic PIP) by Dephosphorylation

Kassner

Lessmann²,

Wasner³

1999

Biological Chemistry

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The cAMP antagonist, prostaglandylinositol cyclic phosphate (cyclic PIP), is synthesized from prostaglandin E and activated inositol phosphate. From various tissues only that amount of cyclic PIP can be isolated that constitutes the difference between synthesis and degradation. In order to overcome this drawback, the cyclic PIP degrading enzyme or enzymes had to be characterized prior to searching for inhibitors. Cyclic PIP degrading activities have been found in all rat tissues tested, and are lowest in brain (380 pmol ؋ min -1 ؋ g -1 wet weight) and highest in liver (1460 pmol ؋ min -1 ؋ g -1 wet weight). They are associated primarily with particulate structures of the cells, but not with the plasma membrane. There appear to be at least two different enzymatic activities involved in the degradation of cyclic PIP, because there are two pH-optima, one between pH 7 and 8 and another between pH 4 and 5. It is assumed that these activities are located in microsomes and lysosomes. Because prostaglandylinositol is the final product obtained in the degradation of cyclic PIP, a phosphodiesterase and a phosphatase should be involved, which could not yet be identified individually. Like alkaline phosphatase, cyclic PIP-degrading enzymes require Mg 2+ and they are inhibited by heavy metal ions such as mercuric and copper chloride, by sodium fluoride and interestingly, by prostaglandins.

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Biosynthesis of cyclic AMP antagonist in hepatocytes from rats after adrenalin‐ or insulin‐stimulation

Cited by 31 publications

References 9 publications

Two Different Mechanisms for Activation of Cyclic PIP Synthase: by a G Protein or by Protein Tyrosine Phosphorylation

Two Different Mechanisms for Activation of Cyclic PIP Synthase: by a G Protein or by Protein Tyrosine Phosphorylation

Prostaglandylinositol cyclic phosphate (cPIP): a novel second messenger of insulin action. Comparative analysis of two kinds of ‘insulin mediators’

Degradation of the Cyclic AMP Antagonist Prostaglandylinositol Cyclic Phosphate (Cyclic PIP) by Dephosphorylation

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