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:3.6.1.3 (ATPase)
65,361 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We probed possible developmentally related changes in thin filament activity in rat hearts with the aid of calmidazolium (CDZ). CDZ is a calmodulin antagonist that also binds to troponin C and stimulates Ca2+ troponin C-dependent activation of cardiac myofibrillar contractile activity. In paired experiments, we compared the effects of 10, 30, 50, 70, and 100 microM CDZ on Mg2(+)-dependent ATPase activity of myofibrillar preparations from adult and neonatal rat hearts. Over the dose-response curve, the ATPase activity of neonatal myofibrils was significantly less stimulated than was the ATPase activity of the adult preparations. To know whether this difference in response to CDZ was related to differences in the thin or thick filaments, we studied hybrid adult and neonatal myofibrillar preparations. These hybrid myofibrils had native thin filaments, but the thick filaments were displaced with rabbit skeletal myosin. The relative insensitivity of the neonatal preparations to the effect of CDZ was retained in the hybrid myofibrils. This suggested that developmental transitions in the population of thin filament proteins are responsible for the difference between adult and neonatal myofibrils in their response to CDZ. Recently, we and others have reported developmental switching of troponin I isoforms in the rat heart. Since troponin I reacts strongly with troponin C in a Ca2(+)-dependent manner, we speculate that developmentally related changes in troponin I isoforms may contribute to the differential effect of CDZ in neonatal cardiac myofibrils.
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PMID:Developmental difference in the stimulation of cardiac myofibrillar Mg2(+)-ATPase activity by calmidazolium. 214 10

Certain heavy metal actions such as Cd2+ and Pb2+ mimic Ca2+ effectively in stimulating calmodulin (CaM). We now show that these cations also activate skeletal muscle troponin C (TnC), a Ca2(+)-binding protein highly homologous to CaM. Like Ca2+, these cations allow TnC to alter its electrophoretic mobility on polyacrylamide gels, and to bind to phenyl-Sepharose. Moreover, they activate TnC to stimulate myofibrillar ATPase. When TnC was removed from the skeletal myofibrils by treatment with trans-1,2-cyclohexanediamine-N,N,N',N'-tetraacetic acid (CDTA), the ATPase activity was no longer stimulated by the cations. However, after reconstitution of CDTA-treated skeletal myofibril with TnC, the response of ATPase to Ca2+, Cd2+ or Pb2+ was restored. These findings suggest that the activation of myofibrillar ATPase by Cd2+ and Pb2+ is mediated through TnC. The ability of the heavy metals to stimulate TnC-supported ATPase activity correlated quite well with the ability to increase the extent of the myofibrillar superprecipitation. The activation of TnC by Cd2+ or Pb2+ could constitute a possible molecular basis for their toxicity.
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PMID:Activation of troponin C by Cd2+ and Pb2+. 214 67

Changes of contraction and optical anisotropy of isolated skeletal muscle cells from Rana temporaria and Astacus fluviatilis were compared under voltage clamp conditions. The time course of the optical signal from frog muscle was shown to consist of two components which could be attributed to calcium binding both on the sarcoplasmic reticulum Ca-ATPase and troponin C. The optical signal from the crayfish muscle has no distinguishable components, and its onset probably reflects the start of Ca-ATPase activity. This hypothesis is supported by the analysis of effects of some pharmacological agents and conditioning depolarization on tension and optical signal.
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PMID:Voltage dependence of depolarization-contraction coupling processes in skeletal muscle cells. 235 85

A sequence homology has been noted between the carboxyl quarter of the catalytic gamma subunit of phosphorylase kinase and the region of troponin I coded by exon VII. Because this portion of troponin I contains the inhibitory region that interacts with actin and troponin C, we have examined whether the gamma subunit of phosphorylase kinase can functionally mimic troponin I by also interacting with actin and troponin C. We have found that troponin C not only activates the isolated gamma subunit of phosphorylase kinase but also binds with approximately the same affinity as calmodulin. Although actin had no effect on the activity of the gamma subunit alone, it did inhibit the activity of gamma-calmodulin and gamma-troponin C complexes. Conversely, the gamma subunit was able to inhibit actomyosin ATPase in a process that could be overcome by calmodulin. These results suggest that actin and calmodulin (or troponin C) compete for binding to the gamma subunit. Moreover, the structural and functional similarities between the gamma subunit and troponin I suggest that the gamma subunit of phosphorylase kinase may have evolved from the fusion of a protein kinase protogene with a progenitor of exon VII of troponin I.
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PMID:Functional and structural similarities between the inhibitory region of troponin I coded by exon VII and the calmodulin-binding regulatory region of the catalytic subunit of phosphorylase kinase. 240 8

The Ca2+-dependent regulation of contractile protein interactions in cardiac and vascular smooth muscle involves structurally related but distinct Ca2+ binding proteins. In vascular smooth muscle, Ca2+ binds to calmodulin, and Ca2+-calmodulin activates myosin light chain (MLC) kinase with ultimate stimulation of MLC phosphorylation and actin-myosin interactions. The largest class of inhibitors of vascular contractile protein interactions are the calmodulin antagonists which include certain Ca2+ entry blockers. Pharmacologically, some of these agents can be distinguished from pure Ca2+ entry blockers by being more effective vs. vasoconstrictor agents in vitro, less cardiac depressant, and more effective as platelet aggregation inhibitors. An even greater distinction from Ca2+ entry blockers is evident with another series of agents, isoquinolinesulfonamides, which directly inhibit protein kinase activity. Cardiac muscle myofibrillar regulation involves Ca2+ binding to troponin C (TnC). Some cardiotonics, such as Vardax and APP 201-533, increase the Ca2+ sensitivity of cardiac myofibrillar ATPase activity with a concomitant increase in Ca2+ binding to TnC. Several calmodulin antagonists, Ca2+ blockers, and structurally related agents differentially affect cardiac myofibrillar ATPase activity. Potency and efficacy of some of these stimulating agents is markedly greater than Vardax or APP 201-533. Mechanistically, all agents do not affect cardiac MLC phosphorylation, but directly enhance the Ca2+ sensitivity of ATPase activity. However, differential effects on basal and maximum ATPase activity by some agents suggest more complex or additional effects which are related to the type of agent as well as the species (dog vs. hamster). A major subcellular defect in congestive heart failure in various small animal models is a depressed maximum ATPase activity. Thus, a desired goal would be a pharmacological modulator which increases maximum ATPase activity, not necessarily Ca2+ sensitivity. In sum, it is possible to identify agents, Ca2+ binding protein modulators, which directly inhibit vascular smooth muscle and stimulate cardiac muscle contractile protein interactions. The potential advantages/disadvantages of this approach for vasodilator/cardiotonic drug development will have to await future development of novel compounds targeted specifically for these cellular regulatory processes.
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PMID:Pharmacological modulation of cardiac and vascular contractile protein function. 243 41

The interaction of several phenothiazines, benzodiazepines, butyrophenones, polycyclic neuroleptics and tricyclic antidepressants with calmodulin and troponin C was investigated using the fluorescent dye 3,3'-dipropylthiocarbocyanine iodide. In the presence of Ca2+, trifluoperazine (2-trifluoromethyl-10-[3-(1-methylpiperazinyl-4)propyl]-phenothiaz ine dihydrochloride, TFP), which is commonly used as a selective calmodulin inhibitor, half maximally increased the fluorescence of the complex formed of the fluorescent dye with calmodulin at a concentration of 4 mumol/l, and with troponin C at 24 mumol/l. TFP completely inhibited the calmodulin dependent stimulation of cyclic nucleotide phosphodiesterase with a Ki of 4 mumol/l and decreased the maximum Ca2+ dependent troponin C mediated activation of actomyosin ATPase by 35% at a concentration of 100 mumol/l. Metofenazate (3,4,5-trimethoxybenzoate-2-chlor-10-(3-[(beta-oxyethyl) piperazinyl-4]-propyl)phenothiazine diethanesulfonate, methophenazine, MP) produced half maximal fluorescence enhancement of the calmodulin dye complex at a concentration of 6 mumol/l and did not influence the fluorescence of the troponin C dye complex at concentrations of up to 1000 mumol/l. MP also completely inhibited the calmodulin dependent stimulation of phosphodiesterase with a Ki of 7 mumol/l but it had not effect on maximum Ca2+ stimulation of actomyosin ATPase. MP increased the Ca2+ sensitivity of skinned cardiac muscle with an about 10fold lower potency than TFP. In view of these results, we propose MP as a useful tool for distinction between processes mediated by either calmodulin or troponin C.
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PMID:Metofenazate as a more selective calmodulin inhibitor than trifluoperazine. 244 25

We have studied the effect of pimobendan (UD-CG 115 BS) on the electrical, mechanical, and biochemical activity of intact and detergent-skinned preparations of cardiac muscle. Racemic pimobendan increased the contractile force of guinea pig papillary muscle preparations and this positive inotropic action was associated with potentiation of the Ca2+-dependent slow action potentials (APs). However, in the presence of 25 mM [K]0 and maximally activating concentrations of isoproterenol, isometric force was increased further by addition of 50 microM pimobendan with no effect on the slow action potential. Experiments with chemically skinned heart muscle fibers showed that pimobendan, in a dose-dependent manner, increased active tension developed at submaximally activating concentrations of Ca2+. The tension-cost (unit increase in ATPase rate/unit increase in force) was unchanged in the presence of pimobendan. Force-pCa and ATPase-pCa relations of skinned fiber preparations contracting isometrically were shifted to the left by 0.15-0.20 pCa units in the presence of 50 microM pimobendan. The mechanism for this effect was shown to be an increase in the Ca affinity of the regulatory binding sites of troponin C (TNC). These effects are due mainly to the l optical isomer of pimobendan. Addition of either the d or l isomer of pimobendan to preparations. maximally stimulated by 1 microM isoproterenol, did not affect the slow AP parameters, but did increase contractile force to 124% of control by the d isomer and to 184% of control by the l isomer. The Ca2+-sensitizing effect of l-pimobendan on skinned fiber preparations was substantially greater than that of the d isomer.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The positive inotropic effect of pimobendan involves stereospecific increases in the calcium sensitivity of cardiac myofilaments. 247 95

Ca2+ binding to skeletal muscle troponin C in skeletal or cardiac myofibrils was measured by the centrifugation method using 45Ca. The specific Ca2+ binding to troponin C was obtained by subtracting the amount of Ca2+ bound to the CDTA-treated myofibrils (troponin C-depleted myofibrils) from that to the myofibrils reconstituted with troponin C. Results of Ca2+ binding measurement at various Ca2+ concentrations showed that skeletal troponin C had two classes of binding sites with different affinity for Ca2+. The Ca2+ binding of low-affinity sites in cardiac myofibrils was about eight times lower than that in skeletal myofibrils, while the high-affinity sites of troponin C in skeletal or cardiac myofibrils showed almost the same affinity for Ca2+. The Ca2+ sensitivity of the ATPase activity of skeletal troponin C-reconstituted cardiac myofibrils was also about eight times lower than that of skeletal myofibrils reconstituted with troponin C. These findings indicated that the difference in the sensitivity to Ca2+ of the ATPase activity between skeletal and cardiac CDTA-treated myofibrils reconstituted with skeletal troponin C was mostly due to the change in the affinity for Ca2+ of the low-affinity sites on the troponin C molecule.
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PMID:Ca2+ binding to skeletal muscle troponin C in skeletal and cardiac myofibrils. 252 23

CDTA-treatment of rabbit skeletal natural actomyosin resulted in the complete removal of troponin C and the abolishment of Ca2+-activated ATPase activity. The addition of troponin C restored the Ca2+-activated ATPase activity to almost the same extent as that of the intact natural actomyosin. These finding are consistent with those of previous studies on the skeletal and cardiac myofibrils.
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PMID:Removal of troponin C from natural actomyosin of rabbit skeletal muscle by CDTA. 252 70

The interaction of caldesmon with certain Ca-binding proteins was investigated by means of electrophoresis under non-denaturating conditions. In the presence of Ca2+ calmodulin, troponin C and S-100 protein form a complex with caldesmon. No complex formation takes place in the absence of Ca2+. Lactalbumin and pike parvalbumin (pI4.2) do not interact with caldesmon independently of Ca-concentration. Both S-100 protein and calmodulin effectively inhibit phosphorylation of caldesmon by Ca-phospholipid-dependent protein kinase. At low ionic strength S-100 protein reverses the inhibitory action of caldesmon on the skeletal muscle acto-heavy meromyosin ATPase more effectively than calmodulin. It is supposed that in certain tissues and cell compartments the proteins belonging to the S-100 family are able to substitute for calmodulin in the caldesmon-dependent regulation of actin and myosin interaction.
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PMID:Interaction of smooth muscle caldesmon with S-100 protein. 253 Oct 95


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