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)

Gangliosides were recently shown to bind to calmodulin (Higashi, H., Omori, A., and Yamagata, T. (1992) J. Biol. Chem. 267, 9831-9838). This prompted us to investigate the effects of gangliosides on the calmodulin-dependent enzyme, cyclic nucleotide phosphodiesterase. Several species of gangliosides competitively inhibited calmodulin-stimulated phosphodiesterase activity, with GD1b, GT1b, and GD1a being noted to do so particularly (group 1). GM1, GQ1b, and GM2 (group 2) were less inhibitory, and GM3, GM3(NeuGc), GalCer, sulfatide, GgOse4Cer, and oligosaccharide portions of inhibitory gangliosides showed no inhibition in accordance with the binding specificity of calmodulin to gangliosides. Trypsin-activated phosphodiesterase was inhibited by gangliosides with similar specificity, indicating interactions of gangliosides with the enzyme. Inhibition, however, was less than that of calmodulin-dependent activity by these compounds and, in both cases, was eliminated by excess calmodulin. In the absence of calmodulin, group 1 gangliosides at lower concentrations activated the intact enzyme but inhibited it over a certain range of increase in concentration. Ganglioside-dependent modulation of calmodulin-dependent phosphodiesterase activity is thus shown to be due to interactions of gangliosides with both calmodulin and the enzyme, and consequently, ganglioside-calmodulin binding is likely the mechanism for regulation of the enzyme.
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PMID:Mechanism for ganglioside-mediated modulation of a calmodulin-dependent enzyme. Modulation of calmodulin-dependent cyclic nucleotide phosphodiesterase activity through binding of gangliosides to calmodulin and the enzyme. 131 72

8-(p-Chlorophenylthio)-cGMP (8-pCPT-cGMP) and 8-bromo-cGMP were compared with respect to their chemical and biological properties in order to evaluate their potential as selective activators of cGMP-dependent protein kinase (cGMP-PK; EC 2.7.1.37) in intact human platelets. 8-pCPT-cGMP, 8-Br-cGMP and cGMP were shown to be potent and selective activators of purified bovine lung cGMP-PK and of cGMP-PK present in human platelet membranes when compared with the activation of cAMP-dependent protein kinase (cAMP-PK; EC 2.7.1.37). 8-pCPT-cGMP was not hydrolysed by the purified cGMP-stimulated phosphodiesterase (cGS-PDE), cGMP-inhibited phosphodiesterase (cGI-PDE) and Ca(2+)-calmodulin-dependent phosphodiesterase (CaM-PDE), whereas cGMP and, to a lesser extent, 8-Br-cGMP were hydrolysed by all three types of 3',5' cyclic nucleotide phosphodiesterases (EC 3.1.4.17) examined. Also, 8-pCPT-cGMP was not hydrolysed by a human platelet homogenate which contains a high level of the cGMP-specific cGMP-binding phosphodiesterase (cGB-PDE). Additionally, 8-pCPT-cGMP did not activate the cGS-PDE or inhibit the cGI-PDE, whereas half-maximal inhibition of cGI-PDE occurred at 8 microM 8-Br-cGMP. The apparent lipophilicity of 8-pCPT-cGMP was higher than that of 8-Br-cGMP. Extracellular application of 8-pCPT-cGMP to intact human platelets reproduced the pattern of protein phosphorylation induced by sodium nitroprusside (SNP), a cGMP-elevating inhibitor of platelet activation. Quantitatively, 8-pCPT-cGMP was more effective than 8-Br-cGMP in inducing phosphorylation of the 46/50 kDa vasodilator-stimulated phosphoprotein, a major substrate of cGMP-PK in intact platelets. As observed with SNP, pretreatment of human platelets with 8-pCPT-cGMP prevented the aggregation induced by thrombin. The results suggest that 8-pCPT-cGMP is a very potent and selective activator of cGMP-PK in cell extracts and in intact human platelets and, in this respect, is superior to 8-Br-cGMP and other cGMP analogs used for intact cell studies. The data also suggest that inhibition of platelet activation in intact human platelets by nitrovasodilators is mediated by cGMP-PK.
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PMID:Analysis of the functional role of cGMP-dependent protein kinase in intact human platelets using a specific activator 8-para-chlorophenylthio-cGMP. 132 24

Calmodulin-dependent phosphodiesterase was purified to apparent homogeneity from the total calmodulin-binding fraction of bovine heart in a single step by immunoaffinity chromatography. The isolated enzyme had significantly higher affinity for calmodulin than the bovine brain 60-kDa phosphodiesterase isozyme. The cAMP-dependent protein kinase was found to catalyze the phosphorylation of the purified cardiac calmodulin-dependent phosphodiesterase with the incorporation of 1 mol of phosphate/mol of subunit. The phosphodiesterase phosphorylation rate was increased severalfold by histidine without affecting phosphate incorporation into the enzyme. Phosphorylation of phosphodiesterase lowered its affinity for calmodulin and Ca2+. At constant saturating concentrations of calmodulin (650 nM), the phosphorylated calmodulin-dependent phosphodiesterase required a higher concentration of Ca2+ (20 microM) than the nonphosphorylated phosphodiesterase (0.8 microM) for 50% activity. Phosphorylation could be reversed by the calmodulin-dependent phosphatase (calcineurin), and dephosphorylation was accompanied by an increase in the affinity of phosphodiesterase for calmodulin.
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PMID:Phosphorylation and characterization of bovine heart calmodulin-dependent phosphodiesterase. 164 4

A newly designed cyclic AMP (cAMP) analogue, Sp-5,6-dichloro-1-beta-D- ribofuranosylbenzimidazole-3',5'-monophosphorothioate (Sp-5,6-DCl-cBiMPS), and 8-(p-chlorophenylthio)-cAMP (8-pCPT-cAMP) were compared with respect to their chemical and biological properties in order to assess their potential as activators of the cAMP-dependent protein kinases (cAMP-PK) in intact cells. Sp-5,6-DCl-cBiMPS was shown to be both a potent and specific activator of purified cAMP-PK and of cAMP-PK in platelet membranes, whereas 8-pCPT-cAMP proved to be a potent activator of cAMP-PK and cyclic-GMP-dependent protein kinase (cGMP-PK) both as purified enzymes and in platelet membranes. Sp-5,6-DCl-cBiMPS was not significantly hydrolysed by three types of cyclic nucleotide phosphodiesterases, whereas 8-pCPT-cAMP (and 8-bromo-cAMP) was hydrolysed to a significant extent by the Ca2+/calmodulin-dependent phosphodiesterase and by the cGMP-inhibited phosphodiesterase. The apparent lipophilicity, a measure of potential cell-membrane permeability, of Sp-5,6-DCl-cBiMPS was higher than that of 8-pCPT-cAMP. Extracellular application of Sp-5,6-DCl-cBiMPS to intact human platelets reproduced the pattern of protein phosphorylation induced by prostaglandin E1, a cAMP-increasing inhibitor of platelet activation. In intact platelets, Sp-5,6- DCl-cBiMPS was also more effective than 8-pCPT-cAMP in inducing quantitative phosphorylation of the 46/50 kDa vasodilator-stimulated phosphoprotein (VASP), a major substrate of cAMP-PK in platelets. As observed with prostaglandin E1, pretreatment of human platelets with Sp-5,6-DCl-cBiMPS prevented the aggregation induced by thrombin. The results suggest that Sp-5,6-DCl-cBiMPS is a very potent and specific activator of cAMP-PK in cell extracts and intact cells and, in this respect, is superior to any other cAMP analogue used for intact-cell studies. In contrast with 8-pCPT-cAMP, Sp-5,6-DCl-cBiMPS can be used to distinguish the signal-transduction pathways mediated by cAMP-PK and cGMP-PK.
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PMID:Characterization of Sp-5,6-dichloro-1-beta-D-ribofuranosylbenzimidazole- 3',5'-monophosphorothioate (Sp-5,6-DCl-cBiMPS) as a potent and specific activator of cyclic-AMP-dependent protein kinase in cell extracts and intact cells. 165 81

Multiple molecular forms of cyclic nucleotide phosphodiesterase have been characterized in various tissues and cells according to their substrate specificity, intracellular location, and calmodulin dependence. The purpose of this study was to evaluate the possible involvement of different molecular forms of phosphodiesterase in regulating the respiratory burst and lysosomal enzyme release responses of human neutrophils. Treatment with the selective cyclic AMP-specific, cyclic GMP-insensitive phosphodiesterase inhibitors Ro 20-1724 or rolipram, or the nonselective phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine (IBMX), resulted in inhibition of respiratory burst stimulated by the chemoattractants formyl-L-methionyl-L-leucyl-L-phenylalanine (FMLP) (IC50 values: 0.71-17 microM) and complement fragment C5a (IC50 values: 61-93 microM), but did not inhibit phagocytosis-stimulated respiratory burst (less than 10% inhibition at 100 microM). Selective inhibitors of calmodulin-dependent phosphodiesterase (ICI 74,917), calmodulin-insensitive, cyclic GMP-specific phosphodiesterase (M & B 22,948), cyclic GMP-stimulated phosphodiesterase (AR-L 57), or cyclic AMP-specific, cyclic GMP-inhibited phosphodiesterase (amrinone and cilostamide) exhibited little or no inhibitory effect on FMLP- or phagocytosis-stimulated respiratory burst (0-42% inhibition at 100 microM). Regulation of neutrophil activation by phosphodiesterase was also response specific, as Ro 20-1724, rolipram and IBMX were less potent inhibitors of FMLP-induced lysosomal enzyme release (0-14% inhibition at 100 microM). Analysis of human neutrophil preparations confirmed the existence of a cyclic AMP-specific, cyclic GMP-insensitive phosphodiesterase, which was associated with the particulate fraction of the cell. These results demonstrate a role for the cyclic AMP-specific, cyclic GMP-insensitive phosphodiesterase in the regulation of human neutrophil functions, which appears to be both stimulus specific and response specific.
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PMID:Differential inhibition of human neutrophil functions. Role of cyclic AMP-specific, cyclic GMP-insensitive phosphodiesterase. 169 20

Intracellularly perfused neurons of Helix pomatia in which serotonin-induced increase of calcium current (Ica) is mediated by cAMP were studied by the voltage clamp technique. It was established that an increase of the calcium intracellular concentration ([Ca2+]i) caused inhibition of the serotonin (5-HT) effect. The 5-HT effect value at 10(-6) and 10(-7) mol/l [Ca2+]i was 60 and 32% of the control one, respectively. Addition of the calmodulin antagonist (5.10(-5) M trifluoperasine) and phosphodiesterase blockers (5 mM theophylline or 10(-4) mol/l IBMX) sharply reduced the Ca2+ ability to inhibit the 5-HT effect. It is concluded that the Ca(2+)-calmodulin-dependent phosphodiesterase is a key link in the interaction between two signal transduction pathways--Ca2+ and cAMP in modulation of the calcium channel activity.
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PMID:[The effect of intracellular calcium on an increase in the cAMP-mediated calcium current]. 171 24

The inhibitors of the cGMP-inhibited, low-Km cAMP phosphodiesterase--milrinone and OPC 3911--and an inhibitor of a non-cGMP-inhibited low-Km cAMP phosphodiesterase--rolipram--were used to evaluate the functional importance of the two cAMP phosphodiesterase activities in vascular smooth muscle and in platelets. Vinpocetine, an inhibitor of a calcium-calmodulin-dependent phosphodiesterase was also studied. OPC 3911 and milrinone relaxed the contracted rat aorta, inhibited ADP-induced platelet aggregation and also enhanced isoprenaline-induced relaxation as well as the antiaggregatory effects of adenosine. In platelets, OPC 3911 and milrinone increased cAMP levels, but in the rat aorta the increase was significant only for milrinone (OPC 3911 P = 0.062). In both tissues OPC 3911 and milrinone enhanced the increase in cAMP caused by activators of adenylate cyclase (isoprenaline/adenosine). Rolipram had no effects on aggregation or cAMP levels in platelets and no overadditive effects in combination with adenosine. Rolipram had little effect on relaxation and cAMP levels, did not alter isoprenaline-induced relaxation of guanfacin-contracted rat aorta, but showed synergistic effects with isoprenaline in raising cAMP levels. In PGF2 alpha-contracted aorta rolipram enhanced relaxation caused by isoprenaline. Vinpocetine had a relaxant effect without affecting cAMP levels, but had no effect on platelets. These results support the concept that the cGMP-inhibited phosphodiesterase is an important modulator of vascular smooth muscle tone and platelet function. The role of the non-cGMP-inhibited phosphodiesterase in these tissues is less obvious.
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PMID:Effects of isozyme-selective phosphodiesterase inhibitors on rat aorta and human platelets: smooth muscle tone, platelet aggregation and cAMP levels. 217 33

The effects of tetrandrine (Tet) on platelet aggregation and thromboxane A2 (TXA2) generation were studied in rabbit platelet-rich plasma (PRP) prepared by centrifugation. The effects of Tet on calmodulin activity in platelet extracts were also investigated by measuring calmodulin-sensitive phosphodiesterase activity. ADP, collagen or arachidonic acid (AA)-induced platelet aggregation was inhibited by Tet in a dose-dependent manner. TXA2 generation in PRP treated by Tet was markedly decreased in collagen-induced group, but was not altered in AA-induced group, suggesting that the release of AA from platelet phospholipids stimulated by collagen was blocked by Tet. Further experiments showed that the effects of Tet were related to its inhibition of calmodulin-dependent phosphodiesterase activity. There was evidence that the effects originated from its anti-calmodulin properties instead of its direct action on phosphodiesterase.
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PMID:[Effects of tetrandrine on rabbit platelet aggregation, thromboxane A2 generation and calmodulin activity]. 281 4

Calmodulin and calmodulin-dependent functional protein play an important role in the maintenance of lens transparency and homeostasis. In the present study, phosphodiesterase, one of the typical calmodulin-dependent functional proteins, was purified from bovine lens by DEAE-cellulose chromatography, calmodulin-Sepharose 4B chromatography and Superose 12 chromatography. Moreover, calmodulin-dependent phosphodiesterase, and independent phosphodiesterase were separated from crude lens extract using DEAE-cellulose column. The calmodulin-dependent phosphodiesterase was purified 4500-fold with a 0.7% yield; it was a dimer formed with two single polypeptides of 59K as the molecular weight. The enzyme had a higher affinity for cyclic GMP than for cyclic AMP, and functioned at calcium ion concentration above 10(-6) M in the incubation mixture. W-7 as calmodulin antagonist indirectly inhibited the enzyme activity and nifedipine as calmodulin-dependent phosphodiesterase antagonist directly inhibited the enzyme activity. These results suggest that an appearance of calmodulin-dependent phosphodiesterase activity depends on the interrelation between the calcium ion and calmodulin in the lens.
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PMID:Purification and characterization of calmodulin-dependent functional protein, phosphodiesterase, in the lens. 283 93

A series of six beta-adrenergic blocking drugs including propranolol, bufetolol, bunitrolol, pindolol, labetalol and acebutolol were examined for effects on adenylate cyclase, guanylate cyclase and calmodulin-dependent phosphodiesterase from heart. The adrenergic blocking agents had no apparent effects on basal activities of adenylate cyclase, guanylate cyclase and phosphodiesterase. The drugs blocked the enhancement of adenylate cyclase activity by isoproterenol, but not by guanine nucleotide or fluoride. The inhibitory effects of beta-antagonists were overcome by sufficiently large doses of isoproterenol. Sodium azide specifically required catalase whereas NaNO2 required cysteine to activate myocardial guanylate cyclase. Among beta-adrenergic blocking drugs tested, both pindolol and acebutolol inhibited the stimulation of guanylate cyclase by NaNo2 or N-methyl-N'-nitro-N-nitrosoguanidine (MNNG). However, other beta-blocking drugs did not significantly affect the activation by NaN3, NaNO2 and MNNG. Several beta-antagonists, such as labetalol, bunitrolol, pindolol and acebutolol were also effective in blocking the activation of phosphodiesterase by calmodulin. The inhibitory effects of beta-adrenergic blocking drugs, i.e. pindolol and acebutolol upon either nitroso compound-stimulated guanylate cyclase or calmodulin-activated phosphodiesterase display little correlation with their potency as beta-adrenergic blocking agents. These data suggest that beta-antagonists may have another site of action which is not directly related to the control of catecholamine metabolism.
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PMID:Different effects of various beta-adrenoceptor antagonists on adenylate cyclase, guanylate cyclase and calmodulin-dependent phosphodiesterase in heart. 286 Sep 6


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