Computational Approaches in the Development of Phosphodiesterase Inhibitors

SummaryHuman monocytes in vitro respond to various agents (immune complexes, lectins, endotoxin, the divalent ionophore A 23187, 12-0-tetradecanoyl-phorbol 13-acetate [TPA], purified protein derivative [PPD] of Bacille Calmette-Guerin) with an increased synthesis of the protein component of thromboplastin. The effect of cyclic AMP and cyclic GMP on this response has been studied. Dibutyryl-cyclic AMP, prostaglandin E1 and the phosphodiesterase inhibitors 3-butyl-1-methyl-xanthine (MIX) and rac -4-(3-butoxy-4-methoxybenzyl)-2-imidazolidinone (Ro 201724), separately and in combination have a pronounced inhibitory effect on the response to immune complexes and PPD, and a moderate effect on the response to endotoxin and lectins. The effect on TPA response and on the response to A 23187 was slight. Dibutyryl-cyclic GMP (1 mM) gave a slight inhibition of the TPA arid IC response, but had essentially no effect on the response to other inducers. The intracellular cAMP level increased when monocytes were incubated with IC, TPA or A 23187 followed by a decrease to basal levels within 1-2 hr, whereas lectin (PHA) and PPD did not induce such changes. The cAMP response to endotoxin varied. Stimulation with IC induced an increase in monocyte cGMP levels, whereas the other stimulants did not cause such changes.

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Brian Roark & Richard Sproat, Computational approaches to morphology and syntax. (=Oxford Surveys in Syntax and Morphology 4). Oxford and New York: Oxford University Press, 2007. xx+316pp. ISBN10 0-19-927478-9, ISBN 13 978-0-19-927478-9 (paperback), ISBN 10 0-19-927477-0, ISBN 13 978-0-19-927477-2 (hardback).

WORD Structure ◽

10.3366/word.2012.0029 ◽

2012 ◽

Vol 5 (2) ◽

pp. 249-253

Author(s):

Anna Feldman

Keyword(s):

New York ◽

Computational Approaches ◽

Oxford University ◽

Oxford University Press

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Recent Advances in Understanding the Basic Mechanisms of Atrial Fibrillation Using Novel Computational Approaches

10.3389/978-2-88963-184-1 ◽

2019 ◽

Keyword(s):

Atrial Fibrillation ◽

Computational Approaches ◽

Recent Advances

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Stimulation of Ca(2+)-dependent exocytosis of the sperm acrosome by cAMP acting downstream of phospholipase A2

Reproduction ◽

10.1530/reprod/118.1.57 ◽

2000 ◽

pp. 57-68 ◽

Cited By ~ 11

Author(s):

J Garde ◽

ER Roldan

Keyword(s):

Arachidonic Acid ◽

Phospholipase A2 ◽

Phospholipase C ◽

Phosphodiesterase Inhibitors ◽

Dibutyryl Camp ◽

Camp Phosphodiesterase ◽

Ram Sperm ◽

Camp Formation ◽

Stimulation Of

Spermatozoa undergo exocytosis in response to agonists that induce Ca2+ influx and, in turn, activation of phosphoinositidase C, phospholipase C, phospholipase A2, and cAMP formation. Since the role of cAMP downstream of Ca2+ influx is unknown, this study investigated whether cAMP modulates phospholipase C or phospholipase A2 using a ram sperm model stimulated with A23187 and Ca2+. Exposure to dibutyryl-cAMP, phosphodiesterase inhibitors or forskolin resulted in enhancement of exocytosis. However, the effect was not due to stimulation of phospholipase C or phospholipase A2: in spermatozoa prelabelled with [3H]palmitic acid or [14C]arachidonic acid, these reagents did not enhance [3H]diacylglycerol formation or [14C]arachidonic acid release. Spermatozoa were treated with the phospholipase A2 inhibitor aristolochic acid, and dibutyryl-cAMP to test whether cAMP acts downstream of phospholipase A2. Under these conditions, exocytosis did not occur in response to A23187 and Ca2+. However, inclusion of dibutyryl-cAMP and the phospholipase A2 metabolite lysophosphatidylcholine did result in exocytosis (at an extent similar to that seen when cells were treated with A23187/Ca2+ and without the inhibitor). Inclusion of lysophosphatidylcholine alone, without dibutyryl-cAMP, enhanced exocytosis to a lesser extent, demonstrating that cAMP requires a phospholipase A2 metabolite to stimulate the final stages of exocytosis. These results indicate that cAMP may act downstream of phospholipase A2, exerting a regulatory role in the exocytosis triggered by physiological agonists.

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