Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: HUMANGGP:030741 (calmodulin-dependent phosphodiesterase)
 89 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

CI-949 [5-methyl-3-(1-methylethoxy)-1-phenyl-N-1H-tetrazol-5-yl-1H- indole-2- carboxamide, L-arginine salt] inhibits human neutrophil activation in response to stimuli which promote calcium mobilization or calcium influx. This report further examines the effect of CI-949 on phosphoinositide-dependent stimulus-response coupling. At 100 microM, CI-949 had no inhibitory effect on human neutrophil phospholipase C or protein kinase C. In contrast, CI-949 inhibited FMLP-stimulated intracellular calcium mobilization with an IC50 of 8.4 microM. The compound was also a potent calmodulin antagonist, inhibiting calmodulin-dependent phosphodiesterase activity with an IC50 of 31.0 microM. The calmodulin antagonist activity of CI-949 was confirmed by fluorescence spectroscopy. These results demonstrate that CI-949 may function through inhibition of calcium- and calmodulin-dependent signal transduction processes.
 ...
PMID:Inhibition of human neutrophil activation by the allergic mediator release inhibitor, CI-949: mechanism of inhibitory activity. 232 55

The effects of Con A on free cytoplasmic calcium concentrations in the cloned murine mast cell, MC9, have been measured using the fluorescent calcium indicator quin 2. Con A causes a rapid, small yet sustained rise in free cytosolic calcium (up to 245 nM) followed closely by increased 45calcium uptake and more slowly by histamine release. The increases in 45calcium uptake and histamine release require extracellular calcium. However, the Ca2+ influx blockers, nifedipine and verapamil inhibit these responses only at concentrations significantly higher than those used in smooth muscle to oppose potential-dependent events, and diltiazem is inactive. These observations suggest that, in these mast cells, other types of channels control Ca2+ entry. In contrast, the intracellular Ca2+ blocker, TMB-8, inhibits both the Con A-induced histamine release and the Ca2+ changes. The calmodulin antagonists calmidazolium, trifluoperazine and W-7 are also highly effective inhibitors of both the Ca2+ changes and histamine release in direct proportion to their potency against calmodulin-dependent phosphodiesterase, implicating calmodulin in the regulation of stimulus-secretion in MC9 cells. These data imply that histamine release follows increases in intracellular Ca2+ concentration. Free intracellular Ca2+ results from rapid release from internal stores and is followed by a slower but more sustained influx of extracellular Ca2+.
 ...
PMID:The role of a Ca2+/calmodulin dependent plasma membrane Ca2+ channel during concanavalin A activation of MC9 mast cells. 244 80

External ATP causes a passive permeability change in several types of transformed cells and this change is further enhanced by calmodulin antagonists, such as trifluoperazine. However, such drugs also have nonspecific effects on membrane permeability. We have synthesized several new sulfonamide derivatives, which were found to inhibit calmodulin-dependent phosphodiesterase. The drugs also enhanced the ATP-dependent permeability change in CHO-K1 cells, but their effective concentration ranges were wider than those of previously known antagonists, and thus they would be useful for pharmacological use.
 ...
PMID:Inhibitory effects of newly synthesized sulfonamide derivatives on calmodulin-dependent phosphodiesterase activity and their modulation of the external ATP-dependent permeability change in mammalian cultured cells. 255 28

Nafazatrom inhibits, in a dose-dependent way, the amplitude and frequency of the rhythmic contractions induced by oxytocin (4 mU/ml), as well as the methacholine (10(-5) M)- and CaCl2 (10 mM)-induced contractions, and the phasic response to KCl (60 mM); similarly, it inhibits the tonic contraction induced by KCl (60 mM) and oxytocin (10 mU/ml). A single concentration of nafazatrom (10(-4) M) also inhibits the uterine contractions caused by carbachol (10(-4) M) and prostaglandin F2 alpha (10(-6) M). CaCl2 (0.1-10 mM) only partially reverses the inhibition produced by nafazatrom on the KCl-induced tonic contractions. Bay K 8644 (3 x 10(-10)-3 x 10(-7) M) reverses the inhibition by 10(-4) M but not by 3 x 10(-4) M of nafazatrom on the CaCl2-induced contractions. Nafazatrom also inhibits, in a dose-dependent way, the calmodulin-dependent phosphodiesterase activity. Our results would suggest that, independently of its 5-lipoxygenase blocking activity, nafazatrom inhibits the contractions of the rat uterus by inhibiting the calmodulin activity and, presumably, by reducing the influx of extracellular calcium and/or the mobilization of intracellular calcium.
 ...
PMID:Mechanism of nafazatrom-induced inhibition of rat uterus contractions in vitro. 256 Mar 65

The chlorpromazine, a calmodulin inhibitor, has been studied for its action on the contraction force and calcium current of the frog atrium fibres. Chlorpromazine (10(-5) mol/l) was observed to induce maximal increase of the contraction force that 30 min after the agent action amounted to (47.3 + 9.3)% of control. The high concentration of chlorpromazine (10(-4) mol/l) produced irreversible decrease in the contraction force. Chlorpromazine (10(-5) mol/l) increased the calcium current by (27.5 +/- 4.8)%. It is supposed that chlorpromazine increases contraction force and calcium current through the inhibition of calmodulin-dependent phosphodiesterase activity.
 ...
PMID:[Inotropic effect of chlorpromazine on the frog atrium]. 272 41

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.
 ...
PMID:[Effects of tetrandrine on rabbit platelet aggregation, thromboxane A2 generation and calmodulin activity]. 281 4

The calmodulin antagonist W7 and 4 of its analogues were examined for their ability to inhibit human NK cell mediated cytotoxicity. With the exception of one of these compounds, which is extremely hydrophobic, there was a good correlation between the ability of drugs to inhibit human NK antitumour cytotoxicity and calmodulin-dependent phosphodiesterase activity in vitro. The most potent of the compounds, 5-iodo-1-C8, an analogue of W7, has an IC50 of 3 microM upon biological and biochemical assay. This particular compound is both more potent and specific than the parent compound W7, is non-toxic to cells over the range used and is also capable of inhibiting the biological activity of NK cells upon pre-treatment of the effector cells, inferring the mechanism of NK cytotoxicity to be calmodulin dependent.
 ...
PMID:Evidence for the involvement of calmodulin in natural cytotoxicity using a range of calmodulin antagonists of varying potency and improved specificity. 283 53

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.
 ...
PMID:Purification and characterization of calmodulin-dependent functional protein, phosphodiesterase, in the lens. 283 93

Sphingosine is a potent inhibitor of several calmodulin-dependent enzymes. The multifunctional Ca2+/calmodulin-dependent protein kinase, a Ca2+/calmodulin-dependent phosphodiesterase, and smooth muscle myosin light chain kinase are inhibited in vitro at concentrations previously shown to inhibit protein kinase C. Inhibition of each of the enzymes is competitive with calmodulin, suggesting that sphingosine may be a calmodulin antagonist. In the pituitary cell line GH3, sphingosine inhibits the phosphorylation of microtubule-associated protein 2 by the multifunctional Ca2+/calmodulin-dependent protein kinase and the phosphorylation of elongation factor 2 by Ca2+/calmodulin-dependent kinase III. These findings suggest that sphingosine, in blocking the effects of both the Ca2+.calmodulin complex and of diacylglycerol, may be a very effective inhibitor of both branches of the phosphatidylinositol signaling pathway. By extension, caution should be exercised in the use of sphingosine as a diagnostic test for the involvement of protein kinase C in biological processes.
 ...
PMID:Sphingosine inhibits calmodulin-dependent enzymes. 284 4

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.
 ...
PMID:Different effects of various beta-adrenoceptor antagonists on adenylate cyclase, guanylate cyclase and calmodulin-dependent phosphodiesterase in heart. 286 Sep 6


<< Previous 1 2 3 4 5 6 7 Next >>