Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.1.4.1 (phosphodiesterase)
18,767 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

1. The activities of the enzymes involved in the metabolism of cyclic nucleotides were studied in sarcolemma prepared front guinea-pig heart ventricle; the enzyme activities reported here were linear under the assay conditions. 2. Adenylate cyclase was maximally activated by 3mM-NaF; NaF increased the Km for ATP (from 0.042 to 0.19 mM) but decreased the Ka for Mg2+ (from 2.33 to 0.9 mM). In the presence of saturating Mg2+ (15 mM), Mn2+ enhanced adenylate cyclase, whereas Co2+ was inhibitory. beta-Adrenergic amines (10-50 muM) stimulated adenylate cyclase (38+/-2%). When added to the assay mixture, guanyl nucleotides (GTP and its analogue, guanylyl imidophosphate) stimulated basal enzyme activity and enhanced the stimulation by isoproterenol. By contrast, preincubation of sarcolemma with guanylyl imidodiphosphate stimulated the formation of an 'activated' form of the enzyme, which did not reveal increased hormonal sensitivity. 3. The guanylate cyclase present in the membranes as well as in the Triton X-100-solubilized extract of membranes exhibited a Ka for Mn 2+ of 0.3 mM; Mn2+ in excess of GTP was required for maximal activity. Solubilized guanylate cyclase was activated by Mg2+ only in the presence of low Mn2+ concentrations; Ca2+ was inhibitory both in the absence and presence of low Mn2+. Acetylcholine as well as carbamolycholine stimulated membrane-bound guanylate cyclase. 4. Cylic nucleotide phosphodiesterase activities of sarcolemma exhibited both high-and low-Km forms with cyclic AMP and with cyclic GMP as substrate. Ca2+ ions increased the Vmax. of the cyclic GMP-dependent enzyme.
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PMID:Adenylate cyclase, guanylate cyclase and cyclic nucleotide phosphodiesterases of guinea-pig cardiac sarcolemma. 1 Aug 95

1. The role of adenosine 3':5'-phosphate (cyclic AMP) and guanosine 3':5'-phosphate (cyclic GMP) as second messengers for the enzyme secretory response evoked by the autonomic neurotransmitters, noradrenaline and acetylcholine, is examined in this in vitro study on the guinea-pig submandibular gland. 2. Noradrenaline increased enzyme (kallikrein) secretion. The initial stimulation of enzyme release appeared to be dose-dependent. The time course of cumulative kallikrein secretion revealed a complex pattern. Isoprenaline and phenylephrine were almost as potent as noradrenaline in releasing kallikrein. Both propranolol and phentolamine were required to fully inhibit the noradrenaline-stimulated enzyme secretion. 3. The cumulative secretion of kallikrein evoked by acetylcholine was dose-dependent. The onset of secretion showed a significantly greater time-lag than that observed with noradrenaline. Atropine effectively blocked the release of kallikrein by acetylcholine. 4. Dibutyryl cyclic AMP stimulated enzyme secretion. Dibutyryl cyclic GMP caused an initial increase which was not maintained. 5. The cyclic nucleotide phosphodiesterase inhibitors, theophylline and papaverine, increased basal kallikrein secretion. The action of the cyclic phosphodiesterase inhibitors on the secretory response to noradrenaline, acetylcholine, dibutyryl cyclic AMP and dibutyryl cyclic GMP was complex. In general, the increase in enzyme release produced by the secretagogues was additively enhanced by both inhibitors. 6. Omission of calcium inhibited both acetylcholine and dibutyryl cyclic GMP stimulated kallikrein release, but to a lesser degree than that of noradrenaline and dibutyryl cyclic AMP. High concentrations of extracellular calcium (10 mM) appeared to enhance the action of acetylcholine. 7. Noradrenaline produced a rise in the intracellular level of cyclic AMP. The increase preceded the stimulated secretion of kallikrein. Of the various adrenergic agonists, noradrenaline and isoprenaline were the most potent, whereas phenylephrine was significantly less effective in raising basal cyclic AMP values. Acetylcholine was without effect, even in the presence of a cyclic phosphodiesterase inhibitor. 8. Acetylcholine and noradrenaline raised intracellular levels of cyclic GMP only when the tissue incubations were performed in the presence of a cyclic phosphodiesterase inhibitor. The increase in cyclic GMP produced by acetylcholine preceded enzyme secretion. 9. Morphological data substantiated the finding that the in vitro release of kallikrein evoked by the secretagogues was associated with the depletion of secretory granules and vacuolations in acinar cells of the gland slices. 10. The molecular mechanisms which control enzyme secretion in the exocrine submandibular gland are discussed. Models are presented for the role of transmitter-specific cyclic nucleotides and calcium in stimulus-secretion coupling.
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PMID:Stimulus-secretion coupling: role of cyclic AMP, cyclic GMP and calcium in mediating enzyme (kallikrein) secretion in the submandibular gland. 18 62

1. The regulation of adenosine 3':5'-cyclic monophosphate (cyclic AMP) levels by cholinoceptors has been studied in cultured bovine adrenal medullary cells. 2. Acetylcholine (100 microM), nicotine (10 microM) and dimethylphenylpiperazinium (20 microM) each increased cellular cyclic AMP levels 2 to 4 fold over 5 min in the absence of phosphodiesterase inhibitors. The muscarinic agonist acetyl-beta-methylcholine (100 microM) had no effect either on its own or on the response to nicotine. The responses to acetylcholine and nicotine were unaffected by atropine (1 microM) but were abolished by mecamylamine (5 microM). 3. Cellular cyclic AMP increased transiently during continuous exposure to nicotine (1-20 microM), with the largest response seen after 5 min, a smaller response after 20 min, and no change in cyclic AMP levels seen after 90 or 180 min. The maximal response after 5 min stimulation was seen with 5-10 microM nicotine and the EC50 was about 2 microM. In contrast, extracellular cyclic AMP levels did not change after 5 or 20 min stimulation with nicotine, but increased slightly after 90 min and further after 180 min. 4. The cellular cyclic AMP response to nicotine (10 microM) was unchanged or weakly enhanced in the presence of the unselective phosphodiesterase inhibitor, isobutylmethylxanthine, and was unchanged in the presence of rolipram. Nicotine did not interact synergistically with low concentrations of forskolin. The response was however completely abolished in the absence of extracellular Ca2+.
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PMID:Cholinoceptor regulation of cyclic AMP levels in bovine adrenal medullary cells. 138 80

The inhibitory action of the major constituent of Genista tridentata L. (Papilionaceae), 4',5,7-trihydroxyisoflavone (genistein), on contractions induced by agonists and electrical field stimulation of smooth muscle was analysed. Genistein inhibited twitches evoked by electrical-stimulation of strips of guinea-pig ileum with an IC50 value of 34 microM. Genistein (34 microM) inhibited contractions of the guinea-pig ileum by several agonists in a non-selective, antispasmodic action and had no effect on inhibition of 3H-ACh release from ileal myenteric plexus. Genistein (34 microM) produces an increase in cAMP levels of guinea-pig ileum which resulted in a smooth muscle relaxation which leads us to think that there must be a blockade of its phosphodiesterase.
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PMID:Effects of genistein, an isoflavone isolated from Genista tridentata, on isolated guinea-pig ileum and guinea-pig ileal myenteric plexus. 143 90

1. Single guinea-pig ventricular cells were voltage clamped using the patch clamp method combined with the pipette-perfusion technique. The voltage-dependent current systems were mostly blocked, and the background membrane conductance was measured by applying ramp pulses. 2. beta-Adrenergic effectors and related substances such as adrenaline, isoprenaline, forskolin or internal application of cyclic AMP induced a current component which showed a reversal potential near the expected Cl- equilibrium potential as well as an outward rectification in the I-V relation. It is suggested that the activation of this Cl- current was due to phosphorylation of the channel protein or related structure by the cyclic AMP-dependent protein kinase. Coincidentally with the activation of the Cl- current, the membrane capacitance of the cell decreased reversibly. 3. Acetylcholine (ACh) depressed the responses induced by beta-adrenergic stimulation and forskolin, but failed to interfere with the one induced by cyclic AMP. 4. The dose dependence of the Cl- current activation by isoprenaline or forskolin was fitted by the Hill equation, with a coefficient of 1.9 and a half-maximum concentration K 1/2 = 13 nM for isoprenaline, and with a Hill coefficient of 3 and a K 1/2 = 1.2 microM for forskolin. In the presence of 5.5 microM-ACh the dose-response relation shifted to higher doses; K 1/2 was 65 nM for isoprenaline and 3.6 microM for forskolin. 5. Washing out ACh in the presence of isoprenaline frequently caused transient overshoots of the response. When a saturating concentration of isoprenaline was used, this rebound was not observed. 6. The internal application of cyclic GMP enhanced the response of the Cl- current induced by isoprenaline or adrenaline. 7. When cyclic AMP was applied internally, the response was small in most cells. When the cell was superfused with 20 microM-IBMX (3-isobutyl-1-methylxanthine), the Cl- current was consistently induced by the application of cyclic AMP. It is suggested that phosphodiesterase activity strongly buffered the influx of cyclic AMP through the patch pipette tip. 8. We suggest that the compensatory interaction between the beta-adrenergic stimulation and the muscarinic inhibition is at the membrane level, most probably via GTP-binding proteins in activating adenylate cyclase.
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PMID:Beta-adrenergic and muscarinic regulation of the chloride current in guinea-pig ventricular cells. 168 50

Radiotracer (86Rb, 125I) efflux measurements and intracellular microelectrode recording were performed to study the cellular mechanisms that regulate the endogenous ionic conductances in Xenopus oocytes. Addition of isoproterenol (Iso, 10(-5) M) caused a marked increase in 86Rb efflux, with a time course that is in good agreement to Iso-elicited membrane hyperpolarization. Thus, radiotracer efflux measurement appears to be a sensitive assay method to study stimulus-secretion coupling in oocytes. 125I efflux was suppressed by the C1- channel blocker diphenylamine-2-carboxylate, but was insensitive to bumetanide. Elevation of ambient [Ca2+] from 0.4 to 10 mM resulted in an eminent increase in 125I efflux for up to approximately 20 min. Acetylcholine (10(-5) M), which mobilizes cell Ca2+, also enhanced 125I efflux. Iso although increased intracellular cAMP level approximately 2-fold, but showed no stimulatory effect on 125I efflux. Addition of 8-(-4-chlorophenylthio)-cAMP (1 mM), or of forskolin (10(-5) M) plus the phosphodiesterase inhibitor 3-isobutyl-1-methyl-xanthine (2 x 10(-4) M), also failed to enhance 125I efflux. These results suggest that, in sharp contrast to the mechanisms for Cl-conductance regulation in mammalian Cl-secreting epithelia, the endogenous Cl- conductance in Xenopus oocytes is, under normal physiological conditions, primarily regulated by intracellular Ca(2+)- rather than a cAMP-mediated signaling mechanism.
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PMID:Regulation of endogenous chloride conductance in Xenopus oocytes. 171 81

Changes in the EPSC and Ach-current amplitudes of Planorbis corneus LC-1 and RC-1 neurons has been comparatively investigated after the influence on their adenylate cyclase system in order to reveal postsynaptic mechanisms of the heterosynaptic facilitation. Both responses are n-cholinergic and depend on the membrane conductivity for Na+ and K+. Application of 5-HT has led to an increase of the EPSC and ACh current (in most cases) amplitudes by 100-300%. A negligible increase of the EPSC and at the same time a decrease of the Ach-current were observed in 30% of cells. It was, probably, a result of different contribution made by Na+ and K+ to the activation mechanism of the channel-receptor complex conductivity of the nonsynaptic cell membrane. Effects of 5-HT on EPSCs and Ach-current were imitated by actions of the phosphodiesterase blockers and adenylate cyclase activators. Both the blockers and activators depressed the EPSCs and Ach-current. Thus, activation of the adenylate cyclase system by serotonin has promoted development of the postsynaptic mechanisms of heterosynaptic facilitation in command neurons of Planorbis corneus.
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PMID:[Participation of the adenylate cyclase system in the postsynaptic mechanism of heterosynaptic facilitation]. 179 13

[3H]Acetylcholine release from slices of rabbit hippocampus was elicited by electrical field stimulation (360 pulses/3 Hz). Both forskolin, commonly used as a specific activator of adenylate cyclase, as well as 1,9-dideoxy-forskolin, which fails to activate adenylate cyclase, increased the evoked transmitter release in an almost identical manner. In addition, the phosphodiesterase inhibitor, rolipram, and the membrane-permeable analogue of cAMP, 8-Br-cAMP, did not influence acetylcholine release. These data show that forskolin is not specific to adenylate cyclase and that the increase in acetylcholine release in the rabbit hippocampus occurs through a mechanism other than activation of adenylate cyclase.
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PMID:Forskolin modulates acetylcholine release in the hippocampus independently of adenylate cyclase activation. 238 34

Guanylyl-imidodiphosphate, guanosine 5'-tetraphosphate and phosphodiesterase inhibitors, 3-isobutyl-1-methylxanthine and RO 20-1724 significantly increased the basal cAMP output and caused a slight catecholamine (CA) release. These agents accelerated ACh-induced increase in cAMP output followed by a markedly enhanced CA release. Cholera toxin did not cause CA release but markedly enhanced ACh-evoked CA release. These results may suggest that cAMP plays a modulating role in CA release from chromaffin cells.
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PMID:Enhancement of acetylcholine-evoked catecholamine release from perfused dog adrenals by elevating cyclic AMP levels. 241 Dec 35

The effects of muscarinic cholinergic stimulation on beta-adrenergic induced increases in phospholamban phosphorylation and Ca2+ transport were studied in intact myocardium. Isolated guinea pig ventricles were perfused via the coronary arteries with 32Pi, after which membrane vesicles were isolated from individual hearts. Isoproterenol produced reversible increases in 32P incorporation into phospholamban. Associated with the increases in 32P incorporation were increases in the initial rate of phosphate-facilitated Ca2+ uptake measured in aliquots of the same membrane vesicles isolated from the perfused hearts. The increases in 32P incorporation and calcium transport were significantly attenuated by the simultaneous administration of acetylcholine. Acetylcholine also attenuated increases in phospholamban phosphorylation and Ca2+ uptake produced by the phosphodiesterase inhibitor isobutylmethylxanthine and forskolin. The contractile effects of all agents which increased cAMP levels (increased contractility and a reduction in the t1/2 of relaxation) were also attenuated by acetylcholine. The inhibitory effects of acetylcholine were associated with attenuation of the increases in cAMP levels produced by isoproterenol and isobutylmethylxanthine but not by forskolin. Acetylcholine also increased the rate of reversal of the functional and biochemical effects of isoproterenol by propranolol without affecting cAMP levels. These results suggest that cholinergic agonists inhibit the functional effects of beta-adrenergic stimulation in part by inhibition of phospholamban phosphorylation. This inhibition may be mediated by two potential mechanisms: inhibition of beta-adrenergic activation of adenylate cyclase and stimulation of dephosphorylation.
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PMID:Muscarinic cholinergic inhibition of beta-adrenergic stimulation of phospholamban phosphorylation and Ca2+ transport in guinea pig ventricles. 241 74


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