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)

Previous reports have suggested that the physical properties of cell membranes and calcium homeostasis in both the central and peripheral nervous system are changed in Alzheimer's disease (AD). This study has examined the biophysical properties of erythrocyte and platelet membranes by measuring the fluorescence anisotropy of 1,6-diphenyl-1,3,5-hexatriene (DPH) and possible related changes in lipid peroxidation. In addition, we have studied calcium homeostasis by measuring thrombin-stimulated changes in intraplatelet free calcium and Ca2(+)-ATPase activity in AD and healthy age and sex-matched controls. Our results show that there was no significant difference in the fluorescence anisotropy of DPH in erythrocyte membranes isolated from the three groups. There was also no significant difference in lipid peroxidation levels in erythrocytes and plasma of AD patients compared to controls. However, there was a significant reduction in the fluorescence anisotropy of DPH in platelet membranes from AD patients, compared with healthy controls. Recent evident suggests that the increase in platelet membrane fluidity results from alterations in internal membranes. We measured the specific activities of enzyme markers associated with intracellular and plasma membranes in platelets from AD patients and healthy controls. There was a significant reduction in the specific activity of antimycin A-insensitive NADH-cytochrome-c reductase (a specific marker for smooth endoplasmic reticulum (SER)), in AD patients compared to controls, but no change in the specific activity of bis(p-nitrophenyl)phosphate phosphodiesterase (a specific marker for plasma membrane). We have also shown that SER mediated [Ca2+] homeostasis is possibly impaired in AD platelets, i.e., the percentage of thrombin-stimulated increase in intraplatelet [Ca2+] above basal levels was significantly higher in AD compared to matched controls and there were significant reductions in the specific activities of Ca2+/Mg2(+)-ATPase and Ca2(+)-ATPase (but not Mg2(+)-ATPase) in AD platelets. Finally electron microscopic analysis of platelets showed that there was a significant increase in the incidence of abnormal membranes in AD patients compared to controls. The ultrastructural abnormalities seem to consist of proliferation of a system of trabeculated cisternae bounded by SER. These results suggest that both SER structure and function might be defected in AD platelets, which could explain the fluidity changes observed here.
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PMID:Platelet and erythrocyte membrane changes in Alzheimer's disease. 214

Most of the currently available calmodulin (CaM) antagonists inhibit the actions of CaM by binding directly to it. These CaM-binding drugs tend to be relatively nonselective, because they inhibit the interaction of CaM with most, if not all, of its target enzymes. In order to develop more selective CaM antagonists, we synthesized covalent adducts of CaM and several drugs, including chlorpromazine (CPZ), fluphenazine-N-mustard (FNM), and phenoxybenzamine (PBZ), and examined the effects of these adducts on various CaM and Ca2(+)-dependent enzymes. One of the adducts (CPZ-CaM) selectively inhibited the CaM-induced activation of phosphodiesterase and myosin light chain kinase, without affecting the basal activity of either enzyme. The inhibition of these enzymes by CPZ-CaM was competitive with respect to CaM. CPZ-CaM did not inhibit CaM-sensitive Ca2(+)-ATPase or CaM-dependent protein kinase or the CaM-insensitive enzyme protein kinase C. The FNM-CaM and PBZ-CaM adducts did not inhibit the effects of CaM on any of the enzymes, but they selectively activated two of the enzymes; FNM-CaM slightly activated the CaM-dependent protein kinase, and PBZ-CaM slightly activated phosphodiesterase. These results show that certain covalently linked drug-CaM adducts can differentially inhibit or activate various CaM-sensitive enzymes, and they provide further evidence that it may be possible to develop new classes of CaM antagonists that are directed against the CaM recognition sites on CaM-sensitive enzymes.
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PMID:Differential inhibition of calcium-dependent and calmodulin-dependent enzymes by drug-calmodulin adducts. 214 88

The role of 48-kDa protein in visual transduction remains unresolved. Two hypotheses for its role in quenching the light activation of cyclic GMP cascade suggest that the protein binds to either phosphodiesterase or phosphorylated rhodopsin. Since the protein is also reported to bind ATP, we anticipated that the protein may have ATP hydrolyzing activity, and in analogy with the GTP-binding protein of the rod outer segments, such activity may be greatly enhanced by the elements of transduction cyclic GMP cascade, permitting the protein to function cyclically as GTP-binding protein does. We found that purified 48-kDa protein hydrolyzes ATP but at a slow rate of 0.04-0.05 per min. The Km for ATP is about 45-65 microM. The activity is inhibited noncompetitively by ADP with a Ki of about 50 microM. The ATPase activity of 48-kDa protein is not affected by rhodopsin, bleached rhodopsin, phosphorylated rhodopsin, unactivated cyclic GMP phosphodiesterase, or phosphodiesterase (PDE) activated by GMP PNP-bound G-protein. These data show that although 48-kDa protein has ATPase activity, lack of regulation of this activity by the elements of visual transduction makes it unlikely for this activity to have a role in quenching the light activation of cyclic GMP cascade.
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PMID:Photoreceptor rod outer segment 48-kDa protein has ATPase activity. 215 Jul 55

We have shown previously that mercuric chloride (HgCl2) inhibits in vitro vasopressin release from the isolated rat neurohypophysis with maximum inhibition occurring with 0.5 mM HgCl2. Associated with the inhibition of hormone release is an increase in 45Ca+2 uptake, an increase in cytosolic 45Ca+2, and a reduction of 45Ca+2 accumulation by mitochondria in the intact gland. In the present series of studies, the effect of HgCl2 on calmodulin (CM) function in neural tissue preparations is reported. Mercuric chloride (0.5 mM) reduced 45Ca+2 binding to CM purified from bovine neurohypophyses by 20% and inhibited endogenous CM-stimulated Ca,Mg-ATPase activity from rat brain mitochondria in a dose-dependent fashion. Ca,Mg-ATPase activity was inhibited by 50 and 80% with 0.5 and 5.0 mM HgCl2, respectively. CM-stimulation of Ca,Mg-ATPase activity was inhibited by calmidazolium (CMZ) with maximal inhibition seen with 0.1 mM CMZ. Reversibility of the HgCl2 interaction with CM was demonstrated using CM-stimulated phosphodiesterase (PDEase) activity from rat brain. HgCl2 inhibited both basal and CM-stimulated PDEase activity in a dose-dependent manner with maximum inhibition occurring with 1.0 mM HgCl2. Preexposure of CM to an inhibitory concentration (1.0 mM) of HgCl2 resulted in no loss of stimulatory PDEase enzyme activity. From these results, we conclude that HgCl2 reversibly interferes with 45Ca+2 binding to CM and also inhibits CM-regulated Ca+2 pumping enzyme systems in the neurohypophysis. The inhibition of vasopressin release from the intact gland in the presence of HgCl2 thus, may be associated with a disruption of calcium in the neurohypophysis.
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PMID:The effects of mercuric chloride on calmodulin-mediated Ca2+ transport in rat brain. 215 38

In vitro effects of three triorganotins--tributyltin (TBT), triethyltin (TET), and trimethyltin (TMT)--on calmodulin (CaM) activity were studied. Stimulation of Ca2(+)-ATPase of rat brain synaptic membranes and phosphodiesterase (PDE) of bovine brain were assayed as indicators of CaM activity. The rat synaptic membranes were prepared and CaM was depleted by washing with 1 mM EGTA. All the three organotins inhibited the basal as well as CaM-stimulated Ca2(+)-ATPase in a concentration-dependent manner, suggesting their interaction with calcium pump. However, CaM-stimulated Ca2(+)-ATPase was more sensitive than the basal enzyme. The order of potency of the three organotin compounds was TBT greater than TET greater than TMT. The IC50 values of Ca2(+)-ATPase (basal) were 0.63, 35, and approximately 800 microM, respectively, whereas the values for CaM-stimulated Ca2(+)-ATPase were 0.05, 0.8, and 18 microM for TBT, TET, and TMT, respectively. CaM-deficient PDE did not show any sensitivity to these three organotin compounds, while TBT and TET significantly decreased the CaM-stimulated PDE activity. TMT, which was the least effective inhibitor of Ca2+ pump, did not alter PDE activity. Further, the inhibition of CaM-stimulated Ca2(+)-ATPase activity by these organotins could be reversed by excess addition of CaM. These results suggest that the organotins interact with CaM activity, as evidenced by their potent effect on CaM-dependent Ca2(+)-ATPase and PDE activities.
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PMID:Differential effects of triorganotins on calmodulin activity. 215 84

This paper describes two fully automated assays. One for zaprinast, a cGMP specific phosphodiesterase inhibitor, which uses the Gilson-Advanced Automated Sample Processor combination, and the other for an H+/K+ ATPase inhibitor and its sulphone metabolite, which uses direct injection. Both assays were developed to support pharmacokinetic studies at therapeutic doses in small animals as well as in man. Plasma or serum (20-200 microliters) is placed directly into an autosampler and all subsequent manipulations are performed mechanically.
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PMID:Two systems for the automated analysis of drugs in biological fluids using high-performance liquid chromatography. 216 38

1. Liver plasma membranes originating from the sinusoidal, lateral and canalicular surface domains of hepatocytes were covalently labelled with sulpho-N-hydroxysuccinamide-biotin. After solubilization in Triton X-114, treatment with a phosphatidylinositol-specific phospholipase C (PI-PLC), two-phase partitioning and 125I-streptavidin labelling of the proteins resolved by PAGE, six major polypeptides (molecular masses 110, 85, 70, 55, 38 and 35 kDa) were shown to be anchored in bile canalicular membrane vesicles by a glycosyl-phosphatidylinositol (G-PI) 'tail'. 2. Permeabilized 'early' and 'late' endocytic vesicles isolated from liver were also examined. Two polypeptides (110 and 35 kDa) were shown to be anchored by a G-PI tail in 'late' endocytic vesicles. 3. Analysis of marker enzymes in bile-canalicular vesicles treated with PI-PLC showed that 5'-nucleotidase and alkaline phosphatase, but not leucine aminopeptidase and ecto-Ca2(+)-ATPase activities were released from the membrane. A low release and recovery of alkaline phosphodiesterase activity was noted. The cleavage from the membrane of 5'-nucleotidase as a 70 kDa polypeptide was confirmed by Western blotting using an antibody to this enzyme. 4. Antibodies raised to proteins released from bile-canalicular vesicles by PI-PLC treatment, and purified by partitioning in aqueous and Triton X-114 phases, localized to the bile canaliculi in thin liver sections. Antibodies to proteins not hydrolysed by this treatment stained by immunofluorescence the sinusoidal and canalicular surface regions of hepatocytes. 5. Antibodies generated to proteins cleaved by PI-PLC treatment of canalicular vesicles were shown to identify, by Western blotting, a major 110 kDa polypeptide in these vesicles. Two polypeptides (55 and 38 kDa) were detected in MDCK and HepG-2 cultured cells. 6. Since two of the six G-PI-anchored proteins targeted to the bile-canalicular plasma membrane were also detected in 'late' endocytic vesicles, the results suggest that a junction where exocytic and endocytic traffic routes meet occurs in a 'late' endocytic compartment.
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PMID:Priority targeting of glycosyl-phosphatidylinositol-anchored proteins to the bile-canalicular (apical) plasma membrane of hepatocytes. Involvement of 'late' endosomes. 217 97

Antibodies against purified Ca2+-transport ATPase from human erythrocytes were raised in rabbits. Immunodiffusion experiments revealed that precipitating antibodies had been developed. The immunoglobulin fraction inhibited solely the calmodulin-dependent fraction of erythrocyte Ca2+-transport ATPase activity, whereas the basal (in the absence of added calmodulin) activity of the enzyme was not significantly affected by the antibodies. The antibodies produced similar doseresponse curves for the calmodulin- and the oleic acid-stimulated enzyme. However, the immunoglobulin fraction was considerably less effective in inhibiting Ca2+-transport ATPase activated by limited proteolysis. The results obtained with our antibodies are compatible with the interpretation that at least one subpopulation of the antibodies attacks the enzyme at or close to the calmodulin-binding site of the ATPase. The antibodies also inhibited the calmodulin-regulated Ca2+-transport ATPase from pig smooth-muscle plasma membrane, though with lower potency. However, the immunoglobulin fraction failed to suppress pig cardiac sarcoplasmicreticulum Ca2+-transport ATPase activity in the concentration range investigated. In addition, the activity of phosphodiesterase from rat brain, another enzyme modulated by calmodulin, was not at all affected by the immunoglobulin fraction.
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PMID:Antibodies against erythrocyte Ca2+-transport ATPase specifically inhibit the calmodulin-dependent fraction of the enzyme's activity. 240 60

The Na- and Cl-absorbing goby posterior intestinal epithelium is composed predominantly of mitochondria-rich, tall columnar cells. Glass intracellular microelectrode recording technique was applied to absorptive cells of this relatively leaky epithelium to measure apical cell membrane potential difference (psi mc) and apical membrane fractional resistance. As determined by ion-substitution studies, absorptive cells are characterized by a large, Ba2+-inhibitable apical K conductance, which is a major factor determining psi mc and smaller Cl and Na conductances. Inhibition of the apical Na-Cl-coupled influx directly by furosemide or indirectly by the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine produced hyperpolarization of psi mc, consistent with the greater apical membrane conductance to Cl than Na. The urophysial neurosecretory peptide urotensin II, which stimulates Na-Cl-coupled absorption, markedly depolarized psi mc in posterior intestinal tissues from 5% seawater-adapted gobies. This response is consistent with a stimulatory effect of urotensin II at the apical membrane carrier rather than at the basolateral Na-K-ATPase. Urotensin II is without effect on psi mc in tissues from seawater-adapted fish and somatostatin, a natural analogue of urotensin II, is without effect on tissues from fish adapted to either salinity. This specificity parallels that determined using radiotracer fluxes.
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PMID:Ion transport in goby intestine: cellular mechanism of urotensin II stimulation. 241 Nov 49

Milrinone is a new inotropic agent for the treatment of refractory congestive heart failure. Our understanding of the mechanisms(s) of action of this synthetic cardiotonic drug is incomplete. We examined the effects of milrinone and the parent compound amrinone on sarcoplasmic reticulum function (45Ca-uptake and Ca-ATPase); radioligand binding to adenosine, beta-adrenergic, and cholinergic muscarinic receptors; cyclic AMP accumulation; and inhibition of various forms of cyclic AMP phosphodiesterases. Comparisons were made to observe how these effects correlate with the inotropic response of heart. Milrinone was shown to be a potent phosphodiesterase inhibitor that was 40 times more potent than amrinone and 10 times more potent at inhibiting the high-affinity (Km = 0.23 microM) form (Ki = 22 microM) than the low-affinity (Km = 140 microM) form (Ki = 225 microM) of cyclic AMP phosphodiesterase in heart. The potency of milrinone as a phosphodiesterase inhibitor was the same in the presence and absence of calcium. Concentrations of milrinone that increased cyclic AMP accumulation also produced positive inotropy. A comparison of milrinone with amrinone and methylxanthines revealed the order of potency to be isobutylmethylxanthine greater than milrinone greater than theophylline greater than caffeine greater than amrinone. Milrinone and amrinone had no effect on 45Ca-uptake or Ca-ATPase activity in myocyte sarcoplasmic reticulum. However, milrinone did bind weakly to adenosine receptors (KD = 466 microM) but not to cholinergic muscarinic or beta-adrenergic receptors. Also, in combination with isoproterenol high concentrations of milrinone blocked the negative inotropic response to the adenosine agonist phenylisopropyladenosine.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Biochemical mechanisms for the inotropic effect of the cardiotonic drug milrinone. 242 30


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