Prostaglandyl-Inositol Cyclic-Phosphate, A New Second Messenger

Wasner, H.K.; Lemoine, Horst; Junger, E.; Lessmann, M.; Kaufmann, R.

doi:10.1007/978-1-4899-0727-1_16

Cited by 9 publications

(16 citation statements)

References 14 publications

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“…It remained unclear, however, which signal transduction pathway mediates the negative sensitive modulation of A-kinase. Possibly, a mediator (cyclic-prostaglandyl-inositol-phosphate) of the class of inositol phosphates, which are thought to mediate contractile events following stimulation of muscarinic [7,28], histaminergic [12], and serotoninergic receptors [24] in airway smooth muscle, that inactivates the protein kinase in vitro, is involved in the A-kinase inactivation [46].…”

Section: Discussionmentioning

confidence: 99%

Formoterol, fenoterol, and salbutamol as partial agonists for relaxation of maximally contracted guinea pig tracheae: Comparison of relaxation with receptor binding

Lemoine

Overlack

Kohl

et al. 1992

Lung

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In severe asthma attacks beta 2-sympathomimetics lose part of their therapeutic efficiency. To elucidate this loss of efficiency in an experimental model we compared the relaxant potency of salbutamol (SAL), fenoterol (FEN), formoterol (FOR), and (-)-isoprenaline (ISO) in guinea pig tracheae partially and maximally precontracted by 0.1 and 60 mumol/L carbachol, respectively. In partially precontracted tracheae the beta 2-sympathomimetics exerted maximum relaxation in comparison with ISO and low EC50S (nmol/L) for relaxation (SAL, 20; FEN, 5.6; FOR, 0.28; and ISO, 2.5). In maximally precontracted tracheae, however, the beta 2-sympathomimetics were only partial agonists for relaxation with reduced intrinsic activities (%) in comparison to ISO (SAL, 59%; FEN, 61%; FOR, 76%) and significantly increased EC50S (nmol/L) for relaxation (SAL, 130; FEN, 57; FOR, 3.0; ISO, 37). To investigate if the high relaxant potency of FOR is correlated with a higher binding affinity and/or a higher intrinsic activity for adenylate cyclase stimulation than for FEN and SAL, we performed experiments in receptor membranes from guinea pig lung. Binding competition of SAL, FEN, and FOR with [3H]ICI 118,551 for lung beta 2-adrenoceptors yielded dissociation constants (KD) of 320 (SAL), 120 (FEN), and 7.6 (FOR) nmol/L, which exhibited the same ranking as EC50S for relaxation. Concentrations of SAL, FEN, and FOR equivalent to 100 KD of the respective dissociation constants stimulated beta 2-adrenoceptor-coupled adenylate cyclase with different intrinsic activities (%) incomparison to ISO (SAL, 61%; FEN, 63%; FOR, 89%) matching intrinsic activities for relaxation. From these experiments it may be concluded that FOR might improve drug therapy of severe asthma not only due to its long mode of action discovered in clinical studies but also due to its high intrinsic activity and receptor affinity.

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Section: Discussionmentioning

confidence: 99%

Formoterol, fenoterol, and salbutamol as partial agonists for relaxation of maximally contracted guinea pig tracheae: Comparison of relaxation with receptor binding

Lemoine

Overlack

Kohl

et al. 1992

Lung

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“…One alternative assay was to determine if cyclic PIP would antagonize the action of cyclic AMP on cyclic AMP-dependent protein kinase (PKA). It was found that: (a) cyclic PIP inhibits PKA dose-dependently and non-competitive to cyclic AMP and ATP; (b) it inhibits the basal and cyclic AMPactivated PKA as well; (c) it inhibits the holo-enzyme and the separated catalytic subunit C. 7,8,14 Preparing photoaffinity labeled [ 3 H] cyclic PIP and also [ 14 C] cyclic AMP (using the photo-affinity label 2-diazomalonyl chloride 15 ), both photo-affinity labeled compounds were covalently bound to PKA after irradiation with UV at 253.7 nm. After separation of the regulatory R and catalytic C subunits (by SDS-gel electrophoresis), the [ 14 C]-labeled cyclic AMP was only bound to the R subunit, but the [ 3 H]labeled cyclic PIP was bound to both the R and the C subunit (Gebel and Wasner, unpublished), suggesting that cyclic PIP has its binding site close to the cleft between the R and C subunit of the PKA.…”

Section: Inhibition Of Protein Kinase a And Activation Of Protein Smentioning

confidence: 99%

“…As an alternative, tissue homogenates were shaken with chloroform/methanol. 2,10 Subsequent water-extracts contained high nucleotide amounts. A rough calculation showed that the levels of the nucleotides were 10,000-fold higher than that of cyclic PIP in the extract.…”

Section: Inhibition Of Protein Kinase a And Activation Of Protein Smentioning

confidence: 99%

“…After an initial stimulation of hepatocytes with glucagon, on re-stimulation with adrenaline greater cyclic AMP synthesis was found than on the first stimulation with adrenaline. 2 This could indicate that cyclic AMP antagonizes the synthesis of this adenylate cyclase inhibitor (see below). In hepatocytes of diabetic rats, less inhibition of cyclic AMP synthesis was observed than with non-diabetic rats.…”

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confidence: 99%

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Prostaglandylinositol cyclic phosphate, the natural antagonist of cyclic AMP

Wasner

2020

IUBMB Life

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While searching for a counterpart to cyclic AMP, a new compound was found to inhibit adenylate cyclase. It was identified as prostaglandyl-(15-4 0)-myo-inositol (1 0 :2 0-cyclic)-phosphate (cyclic PIP). The substrates for its biosynthesis are prostaglandin E (PGE) and the novel inositol phosphate, guanosine diphospho-4-myoinositol 1:2-cyclic phosphate (n-IP). The basic regulatory properties of cyclic PIP are to inhibit dose-dependently protein kinase A (PKA) and to seven-fold activate protein ser/thr phosphatase holoenzyme. These regulations occur as rapidly as the activation of PKA by cyclic AMP. Such regulatory properties are essential for the meticulous regulation of the equilibrium between the phospho-and de-phospho-form of interconvertible enzymes. The synthesis of cyclic PIP is stimulated by insulin and noradrenaline (α-receptor action). The insulin-stimulated cyclic PIP synthase is active in a tyrosine-phosphorylated state. A comparable characterization of the adrenaline-stimulated cyclic PIP synthase is still incomplete. In streptozotocin-diabetic rats, the hormonal stimulation of cyclic PIP synthesis decreases with time. Cyclic PIP synthesis is activated by biguanides as metformin two to four-fold and by antihypertensive drugs twofold. Inhibition of cyclic PIP synthesis leads to a metabolic state as observed in early-stage type-2 diabetes. In summary, all living cells synthesize cyclic PIP, which switches on anabolism, whereas cyclic AMP triggers catabolism.

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“…Another insulin-sensitive compound, also identified in the 1970s, was initially termed 'cAMP antagonist', and was shown to be a prostaglandylinositol cyclic phosphate (cPIP) [16]. This discovery was based on the ideas of Earl Sutherland who hypothesized the existence of an intracellular regulator that antagonizes the action of cAMP (reviewed in [17]). …”

Section: Introductionmentioning

confidence: 98%

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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Prostaglandyl-Inositol Cyclic-Phosphate, A New Second Messenger

Cited by 9 publications

References 14 publications

Formoterol, fenoterol, and salbutamol as partial agonists for relaxation of maximally contracted guinea pig tracheae: Comparison of relaxation with receptor binding

Formoterol, fenoterol, and salbutamol as partial agonists for relaxation of maximally contracted guinea pig tracheae: Comparison of relaxation with receptor binding

Prostaglandylinositol cyclic phosphate, the natural antagonist of cyclic AMP

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

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