Evidence against a requirement for phospholipid methylation in adenylate cyclase activation by hormones

Schanche, Jon-Sverre; Øgreid, D; Døskeland, Stein Ove; Refsnes, Magne; Sand, Tor‐Erik; Ueland, Per Magne; Christoffersen, Thoralf

doi:10.1016/0014-5793(82)80433-x

Cited by 21 publications

(9 citation statements)

References 34 publications

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“…the conversion of phosphatidylethanolamine into phosphatidylcholine (Hirata et al, 1979;Hirata & Axelrod, 1980). However, this is controversial since in different cell types it has been shown that phospholipid methylation is not directly related to adenylate cyclase activities (Colard & Breton, 1981;Padel et al, 1982) and is not ©D The Macmillan Press Ltd 1987 involved with whole cell activation (Randon et al, 1981;Schanche et al, 1982;Moore et al, 1982;Benyon et al, 1986). We previously demonstrated that platelet activation can be inhibited by the methylation inhibitors (Randon et al, 1981;, by mechanisms other than interference with phospholipid methylation, such as protein methylation (reviewed by O'Dea et al, 1981).…”

Section: Introductionmentioning

confidence: 99%

Blockade by methylation inhibitors of the anaphylactic response of guinea‐pig lung strips

Randon

Lefort

Vargaftig

1987

British J Pharmacology

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The combination of two methylation inhibitors 3‐deazaadenosine (10−4 or 4 × 10−4 m) plus l‐homocysteine (2 × 10−4 m) caused a time‐dependent inhibition of antigen‐induced contraction, formation of thromboxane B2 (TxB2) and release of histamine from lung parenchyma strips taken from guinea‐pigs actively sensitized with ovalbumin (OA). The methylation inhibitors also prevented the lung strip contractions induced by the mediators platelet‐activating factor (Paf‐acether, 10−6 m), leukotriene D4 (LTD4, 10−8 and 3 × 10−8 m), and in part to arachidonic acid (10−6 and 10−5 m), under conditions where the contractions to histamine (10−6‐10−4 m) were virtually unaffected. TxB2 formation induced by these mediators or by OA was more affected by the methylation inhibitors than the lung strip contractions, indicating that prostaglandin formation is more sensitive to these inhibitors than the myotropic activity. In contrast, the suppressive effect of the methylation inhibitors on histamine secretion by parenchyma lung strips induced by OA followed the inhibition of the contraction. These results show that inhibitors of methyltransferases interfere with the myotropic responses and with the release of mediators by actively sensitized guinea‐pig lung strips stimulated with antigen, and suggest a major role for a methylation process in mediating the contraction of and mediator release by the lung parenchyma.

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Section: Introductionmentioning

confidence: 99%

Blockade by methylation inhibitors of the anaphylactic response of guinea‐pig lung strips

Randon

Lefort

Vargaftig

1987

British J Pharmacology

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“…Contrary to our findings, Padel et al found that the activity of receptor-stimulated adenylate cyclase in isolated parotid microsomal membranes was not inhibited or stimulated by S-adenosylhomocysteine or by the addition of S-adenosylmethionine, and amylase secretion was not inhibited by inhibitors of methyltransferase. In other studies the transformation of phosphatidylethanolamine into phosphatidylcholine in rat liver plasma membranes, was not associated with modifications of basal, NaF, or GTP-glucagon stimulated adenylate cyclase activities [29], and 3-deazaadenosine did not impair the cAMP response to glucagon, adrenaline, or isoprenaline in isolated hepatocytes [30].…”

Section: Discussionmentioning

confidence: 97%

Membrane Phospholipid Methylation is Associated with Surfactant Secretion in Rabbit Type II Alveolar Epithelial Cells

Kd¹,

Finkelstein²,

Dl³

1989

Experimental Lung Research

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We investigated the involvement of membrane phospholipid methylation in receptor-mediated secretion of surfactant in adult rabbit type II alveolar epithelial cells (type II pneumocyte). Phospholipid methyltransferase activity was found in type II pneumocyte microsomes. Cell cultures of adult rabbit type II pneumocytes were then used to assay methyltransferase activity in the presence of the beta-adrenergic agonist, terbutaline, and the methyltransferase inhibitor, 3-deazaadenosine. Terbutaline predictably stimulated adenylate cyclase activity and surfactant secretion. It was also found to stimulate incorporation of methyl groups into phosphatidylcholine and to increase beta-adrenergic receptor availability as assayed by binding of dihydroalprenolol (DHA). Surfactant secretion, as well as adenylate cyclase activity, were stimulated by terbutaline and were inhibited by 3-deazaadenosine. 3-Deazaadenosine did not inhibit DHA binding. These results suggest that phospholipid methylation plays a role in stimulus-secretion coupling in adult rabbit type II pneumocytes.

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“…In some cells systems 3-DAA + L-HC raise cAMP levels [9,10], It is possible that increased cAMP in the lung parenchymal strips could reduce the contractile effects of LTD4. However, neither 3-DAA + L-HC, nor MDL 28,842 + L-HC, nor 3-DAA + MDL 28,842 + L-HC significantly altered the levels of cAMP or cGMP.…”

Section: Discussionmentioning

confidence: 99%

“…In addi tion, in some cells, 3-DAA can be metabolized to 3-deazaadenosine 5'-nucleotides [8]. Inter pretation of the data of Randon et al [5] is also complicated by the fact that 3-DAA and L-HC have been shown to raise cyclic AMP (cAMP) levels in several cell systems [9,10], an effect which should lead to inhibition of contractile responses. The availability of a novel, potent and specific inhibitor of SAH hydrolase, MDL 28,842, (Z)-9-(5-deoxy-5-fluoro-B-Derythro-pent-4-enofuranosyl) adenine [11], has made it possible to test whether increased tissue levels of SAH alone inhibit the contrac tile effects of LTD4 on guinea-pig lung paren chymal strips, whether 3-DAA requires con version to 3-deazaadenosylhomocysteine to inhibit contractile responses and whether the activity of SAH hydrolase regulates the con tractile activity of LTD4 in guinea-pig lung parenchymal strips.…”

Section: Introductionmentioning

confidence: 99%

S-Adenosylhomocysteine Levels Are Not Involved in the Spasmolytic Activity of 3-Deazaadenosine in Guinea-Pig Lung Parenchyma

Gieske¹,

Doherty²,

Raddatz³

et al. 1991

Pharmacology

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The effects of two S-adenosylhomocysteine (SAH) hydrolase inhibitors, MDL 28,842 and 3-deazaadenosine (3-DAA), on the tissue levels of SAH, cAMP and cGMP and on the contractile responses to leukotriene D₄ and histamine were compared in guinea-pig lung parenchyma. MDL 28,842 and 3-DAA (both in the presence of L-homocysteine) increased tissue levels of SAH to the same degree, indicating that both compounds had inhibited SAH hydrolase. However, only 3-DAA inhibited the contractile response of the lung parenchyma. The spasmolytic activity of 3-DAA was inhibited by co-incubation with MDL 28,842, suggesting that 3-DAA must be metabolized by SAH hydrolase, probably to 3-deazaadenosylhomocysteine, in order to exert its effect. 3-DAA did not elevate tissue levels of cAMP or cGMP. Although the mechanism by which 3-DAA exerts its spasmolytic effects is unknown, direct inhibition of methyltransferase is a plausible explanation. These data indicate that SHA levels do not regulate the contractile response of guinea-pig lung parenchyma.

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Evidence against a requirement for phospholipid methylation in adenylate cyclase activation by hormones

Cited by 21 publications

References 34 publications

Blockade by methylation inhibitors of the anaphylactic response of guinea‐pig lung strips

Blockade by methylation inhibitors of the anaphylactic response of guinea‐pig lung strips

Membrane Phospholipid Methylation is Associated with Surfactant Secretion in Rabbit Type II Alveolar Epithelial Cells

S-Adenosylhomocysteine Levels Are Not Involved in the Spasmolytic Activity of 3-Deazaadenosine in Guinea-Pig Lung Parenchyma

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