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)

Cyclopiazonic acid (CPA) has been reported to inhibit the Ca(2+)-ATPase of the sarcoplasmic reticulum (SR) in skeletal and smooth muscle. In the present study the effect of CPA on [Ca2+]i and force in rat urinary bladder smooth muscle was examined. The fluorescent Ca2+ indicator Fura-2 was used to monitor intracellular Ca2+, simultaneously with isometric force production. Addition of CPA to unstimulated muscles bathed in 2.5 mM Ca2+ containing Krebs solution resulted in a significant and sustained increase in [Ca2+]i from 99 +/- 7 to 273 +/- 51 nM. This increase in [Ca2+]i was dependent upon the presence of extracellular Ca2+ since when CPA was added to muscles in Ca(2+)-free media it produced only a small, transient increase in [Ca2+]i that was not sustained. Peak force levels produced by transmural stimulation, carbachol and high KCl solution were not altered by the presence of CPA, however, the increase in [Ca2+]i associated with these contractions was larger when CPA was present. In response to transmural stimulation, the times taken for both force and [Ca2+]i to rise to 50% of their peak values were attenuated in the presence of CPA. Conversely, there was no effect of CPA on the times taken for force or [Ca2+]i to fall to 50% of their stimulated values upon the cessation of stimulation. Under control conditions both carbachol and high KCl could initiate transient increases in [Ca2+]i and force in the absence of extracellular Ca2+. In the presence of CPA, the response to carbachol was virtually completely inhibited, however, the response to high KCl was only partially inhibited. The ability of CPA to inhibit the carbachol response in Ca(2+)-free media suggests that this response is due to release of Ca2+ from the SR. The incomplete inhibition of the response to KCl indicates other Ca2+ storage sites may also be mobilised by sarcolemmal depolarisation. Although the mechanism whereby CPA induces a large, sustained rise in [Ca2+]i remains unknown, the data lend support to the suggestion that depletion of intracellular Ca2+ storage sites may activate a Ca2+ entry pathway across the sarcolemma.
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PMID:Effects of cyclopiazonic acid on [Ca2+]i and contraction in rat urinary bladder smooth muscle. 803 95

Membrane currents and contractions evoked by acetylcholine (ACh) in freshly dissociated canine tracheal myocytes were investigated using the nystatin perforated-patch recording technique. In cells held at -60 mV in the presence of nifedipine, ACh evoked inward current (IACh) and contraction. Caffeine mimicked the effects of ACh. IACh and contractions could be evoked 3-4 min after removing external Ca2+ but were abolished by prolonged exposure to Ca(2+)-free media. Both responses were restored within minutes of reintroduction of Ca2+, even though the cells were held at -60 mV in the presence of nifedipine. IACh and ACh-evoked contractions were also reversibly abolished by continued exposure to caffeine. Cyclopiazonic acid (CPA), a blocker of the sarcoplasmic reticulum (SR) Ca(2+)-ATPase, reduced IACh by > 95% within 15 min but had little or no effect on the contractile responses evoked by ACh. IACh was restored after washout of CPA even though cells were held at -60 mV. After depleting the Ca2+ store with the use of CPA, depolarization of the membrane to +10 mV immediately before application of ACh led to a partial restoration of IACh. This restorative effect of depolarization was potentiated by Bay K 8644 and antagonized by nifedipine. In conclusion, IACh and contractions in canine tracheal myocytes are mediated by Ca2+ released from an internal store that can be depleted by prolonged removal of extracellular Ca2+, prolonged exposure to caffeine, or by blockade of the SR Ca(2+)-ATPase. At least two Ca2+ influx pathways appear to contribute to refilling of the internal store: one pathway that is not activated by depolarization or ACh and a second involving dihydropyridine-sensitive voltage-activated Ca2+ channels that may be in direct contact with the SR (i.e., conduct extracellular Ca2+ directly into the SR, bypassing the cytosol).
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PMID:Emptying and refilling of Ca2+ store in tracheal myocytes as indicated by ACh-evoked currents and contraction. 823 12

Cyclopiazonic acid (CPA), a mycotoxin from Aspergillus and Penicillium, has been described as a highly selective inhibitor of Ca(2+)-ATPase in the sarcoplasmic reticulum (SR) in skeletal and smooth muscles but no reports at present deal with the effect of CPA in cardiac muscle. In the present study, we examined the inotropic effect of CPA on adult and neonatal rat myocardia, the contractions of which are known to be highly dependent on Ca(2+)-release from the sarcoplasmic reticulum and transsarcolemmal Ca(2+)-influx, respectively. CPA (30 microM) produced a negative inotropic effect in adult preparations, accompanied by marked prolongation of the contraction duration. In contrast, CPA had minimum effects on neonatal myocardium. Thus we have demonstrated that CPA exerts negative inotropic effects on adult myocardium probably through inhibition of SR function.
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PMID:Possible action of cyclopiazonic acid on myocardial sarcoplasmic reticulum: inotropic effects on neonatal and adult rat heart. 846 51

Following mobilization with the inositol 1,4,5-trisphosphate (IP3)-generating agonist bradykinin, Ca2+ stores in neuroblastoma x glioma hybrid, NG108-15 cells require extracellular Ca2+ to refill. The process by which this store refills with Ca2+ was characterized by recording bradykinin-induced intracellular free Ca2+ concentration transients as an index of the degree of refilling of the store. Cyclopiazonic acid, a microsomal Ca2+ ATPase inhibitor, reversibly depleted intracellular Ca2+ stores in these cells, but did not recruit detectable Ca2+ influx, suggesting that these cells lack substantial capacitative Ca2+ entry. The paucity of voltage-sensitive Ca2+ channels in undifferentiated NG108-15 cells, suggested that a channel analogous to that proposed to mediate capacitative Ca2+ entry in nonexcitable cells might assist refilling IP3-sensitive Ca2+ stores in these cells. The possibility that compounds shown previously to inhibit capacitative Ca2+ entry in nonexcitable cells might inhibit the refilling of the IP3-sensitive store in NG108-15 cells was explored. The IP3-sensitive store was depleted by exposure to bradykinin, allowed to refill briefly in the presence of the test compound and then challenged again with bradykinin to evaluate the degree of refilling of the store. The imidazole derivatives, econazole (10 microM), L-651582 (10 microM) and SKF 96365 (20 microM), all completely blocked the bradykinin-induced Ca2+ response. Calmodulin antagonists, W-7 (100 microM) and trifluoperazine (10 microM), were also effective, although at concentrations well above those required to inhibit calmodulin. Because of the high concentrations required to inhibit bradykinin responses, the possibility that these agents might have additional effects was explored. Compounds were tested in a paradigm in which the store was preloaded with Ca2+ before treatment. All of these agents depleted, at least partially, the preloaded store. Econazole was the least effective of the compounds tested for releasing stores, although it was comparable to the other compounds for inhibition of refilling. Although NG108-15 cells refill intracellular Ca2+ stores by a plasmalemmal Ca2+ leak, this leak shares a pharmacology similar to the capacitative Ca2+ entry pathway described for nonexcitable cells.
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PMID:Pharmacologic characterization of refilling inositol 1,4,5-trisphosphate-sensitive Ca2+ stores in NG108-15 cells. 875 Sep 56

1. We have investigated the internal Ca2+ store and its ability to affect contraction by simultaneously measuring force and Ca2+ in the ureter from guinea-pig and rat. Both species responded in a similar manner to electrical stimulation and depolarization with high-K+, generating plateau-type action potentials and increasing intracellular calcium ([Ca2+]i) and force. 2. In the guinea-pig, carbachol had no effect on [Ca2+]i and force in the resting ureter. In contrast, resting rat ureter always responded with a large [Ca2+]i rise and maintained force to carbachol in Ca(2+)-containing solution, and in Ca(2+)-free solution it showed a transient increase in [Ca2+]i and force. This Ca2+ release and force development was also present in both polarized and high-K(+)-depolarized preparations and was insensitive to nifedipine, suggesting the presence of a receptor-coupled pathway of Ca2+ release in rat ureter. 3. Caffeine was able to produce a release of Ca2+ from the internal store of guinea-pig ureter and elicit contraction. However, rat ureter failed to respond to caffeine. In the presence of La3+, the caffeine response in the guinea-pig ureter and carbachol response in the rat ureter, elicited in Ca(2+)-free solutions, were always increased and prolonged and could be repeatedly evoked, suggesting similarity in Ca2+ uptake behaviour of the store in both species. 4. Ryanodine blocked the caffeine responses of the guinea-pig ureter elicited both in Ca(2+)-containing and Ca(2+)-free solutions, both in the absence and presence of La3+. However, ryanodine failed to prevent the rat ureter responding to carbachol, suggesting that carbachol was releasing Ca2+ from a ryanodine-insensitive channel in the sarcoplasmic reticulum (SR). 5. Cyclopiazonic acid, which inhibits the SR Ca(2+)-ATPase, abolished the effects of both caffeine and carbachol in Ca(2+)-free solutions in guinea-pig and rat, respectively. 6. We conclude that there is a major difference in the mechanisms of Ca2+ release in the internal Ca2+ store of smooth muscle from guinea-pig and rat ureter. The data suggest that the guinea-pig store is purely a calcium-induced calcium release (CICR)-type store and that the rat store is a pure receptor-operated Ca2+ store.
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PMID:Major difference between rat and guinea-pig ureter in the ability of agonists and caffeine to release Ca2+ and influence force. 884 29

Cyclopiazonic acid (selective blocker of the internal Ca+2 pump) evoked tonic contraction in canine bronchial smooth muscle (BSM) and tracheal smooth muscle. This contraction was biphasic, including an initial component that was relatively insensitive to blockade of Ca+2 influx (e.g., removal of external Ca+2; nifedipine; hyperpolarization using lemakalim) followed by a component that was sensitive to all such interventions. In BSM, but not in tracheal smooth muscle, electrical field stimulation (EFS) evoked relaxations that were not affected by interventions designed to prevent release of autacoids from nerve endings or the epithelium, Na+/Ca+2 exchange or Ca(+2)-ATPase activities (internal or plasmalemmal). EFS evoked little or no relaxant response in carbachol-precontracted BSM in the presence of propranolol. After Ca+2 was replaced with Sr+2, however, carbachol evoked comparable contraction after which EFS evoked non-neurogenic relaxations. We found that the EFS-evoked relaxations were abolished by TEA or high KCI, were reduced significantly by charydotoxin or quinine, were reduced partially by ouabain and were unaffected by removal of external K+, by apamin or by glybenclamide. In addition, the relaxations were reduced significantly by the free radical scavenger N-acetylcysteine, were mimicked by H2O2 but were unaffected by superoxide dismutase or catalase. These observations suggest that the cyclopiazonic acid-evoked contraction involves pharmacomechanical coupling mechanisms (i.e., Ca(+2)-release) initially, followed by electromechanical coupling (i.e., voltage-dependent Ca+2 influx). After depletion of the internal Ca+2 store (e.g., by cyclopiazonic acid or Sr+2), EFS is able to evoke in BSM (but not in tracheal smooth muscle) relaxations that seem to involve opening of K+ channels (including those of the large-conductance Ca(+2)-dependent type) by EFS-liberated free radicals.
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PMID:Non-neurogenic electrically evoked relaxation in canine airway muscle involves action of free radicals on K+ channels. 893 Jan 88

Ca2+ efflux from frog muscle sarcoplasmic reticulum (SR) vesicles was studied by measuring external free [Ca2+] using Fluo-3 fluorescence. Light SR vesicles were preloaded with Ca2+ in the presence of ATP and inorganic phosphate (Pi). Calcium pump reversal was activated by either depletion of the medium ATP by apyrase in the presence of 20 mM Pi, or resuspending preloaded vesicles in an ATP-free solution containing 1 mM ADP and 20 mM Pi. Cyclopiazonic acid (CPA) and thapsigargin (TG), at concentrations of 2.5 microM, which completely inhibit Ca2+ uptake, both inhibited the pump reversal efflux almost completely. When active Ca2+ uptake was stopped by either ATP-depletion or addition of CPA, a leak efflux of 6-7 nmole/mg/min was recorded. TG (2.5 microM) reduced this leak by over 50%, suggesting that TG, but not CPA, can slow the passage of calcium ions through the Ca(2+)-ATPase passive channel.
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PMID:Ca2+ effluxes from the sarcoplasmic reticulum vesicles of frog muscle: effects of cyclopiazonic acid and thapsigargin. 893 55

We investigated Ca2+ handling in airway smooth muscle (SM) using fura 2 fluorescence, ion currents, and contractions as indexes of intracellular Ca2+ concentration ([Ca2+]i). Carbachol evoked a transient elevation of [Ca2+]i, the magnitude of which was smaller and the rate of decay faster at 37 degrees C, indicating that some temperature-sensitive mechanism contributed to recovery. Removal of external Na+ had no effect on agonist-evoked Ca2+ transients or contractions or on spontaneous Ca(2+)-dependent K+ currents. Cyclopiazonic acid, a selective inhibitor of the sarcoplasmic reticulum (SR) Ca(2+)-ATPase, evoked a transient elevation of [Ca2+]i and contraction, markedly slowed recovery of the cholinergic Ca2+ transient, and depleted the SR. Sodium vanadate evoked a sustained elevation of [Ca2+]i and markedly slowed the decay of the cholinergic Ca2+ transient. We conclude that, in canine airway SM, 1) Na+/Ca2+ exchange makes at best only a minor contribution to Ca2+ homeostasis, 2) the SR Ca(2+)-ATPase compensates for spontaneous and agonist-triggered release of Ca2+, and 3) [Ca2+]i homeostasis involves some other extrusion pathway, likely the plasmalemmal Ca(2+)-ATPase.
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PMID:Regulation of [Ca2+]i in canine airway smooth muscle by Ca(2+)-ATPase and Na+/Ca2+ exchange mechanisms. 927 43

The action of cyclopiazonic acid, the putative inhibitor of the Ca(2+)-ATPase of endoplasmic reticulum, on phenylephrine-evoked-isometric contractions in rat isolated mesenteric arteries were investigated. Cyclopiazonic acid (3 microM) induced an initial relaxation followed by rhythmic contractions of the phenylephrine-precontracted arteries with intact endothelium. Removal of endothelium abolished the effect of cyclopiazonic acid. Pretreatment of tissues with NG-nitro-L-arginine (100 microM) abolished the initial relaxation but not the rhythmic contractions. Indomethacin and glibenclamide did not affect the cyclopiazonic acid-induced response. Charybdotoxin (100 nM) converted the cyclopiazonic acid-induced rhythmic contractions to the sustained tension in the absence or presence of NG-nitro-L-arginine (100 microM). Pretreatment of charybdotoxin (100 nM) abolished cyclopiazonic acid-induced rhythmic activity but not the initial relaxation. Nifedipine (10 nM) abolished the effect of cyclopiazonic acid. Moderate increase of extracellular K+ (20 mM) reduced the initial relaxation but completely abolished rhythmic contractions induced by cyclopiazonic acid. The remaining relaxation was reversed or prevented by NG-nitro-L-arginine (100 microM). The results of the present investigation indicate that cyclopiazonic acid caused endothelium-dependent response in rat isolated mesenteric arteries probably by releasing nitric oxide responsible for the initial relaxation, and probably by releasing endothelium-derived hyperpolarizing factors primarily responsible for activation of charybdotoxin-sensitive K+ channels and induction of rhythmic contractile activity.
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PMID:Endothelium-dependent rhythmic contractions induced by cyclopiazonic acid in rat mesenteric artery. 928 18

1. After the washing out of the first caffeine, the second 25 mM caffeine-induced tension was about 50% of the first response in tenia coli. Cyclopiazonic acid (CPA), a specific sarcoplasmic reticulum Ca(2+)-ATPase blocker, almost inhibited the contraction to the next application of caffeine after the washing out caffeine in the presence of CPA. The peak tension to caffeine increased after the pretreatment with 10 mM K+ for 1 min. After pretreatment with K+ in the presence of 10(-7) M nifedipine (only phasic response), the tension to caffeine also increased. 2. The response to caffeine was rapidly reduced after incubation in a Ca(2+)-free medium and was abolished after 6 min of incubation. However, the response to caffeine in Ca(2+)-free medium 30 sec. after pretreatment with 10 mM K+ in normal Ca medium was larger. 3. These results suggest that, when the cell membrane is in the resting state, Ca2+ enters the cytoplasm by a leaky pathway and enters storage sites through Ca(2+)-ATPase. Furthermore, when the cell membrane is depolarized for a short period (less than 1 min), Ca2+ entry occurs, leading to refilling of the Ca2+ storage sites utilized by caffeine. The retention of Ca2+ in the storage sites in the Ca(2+)-free condition in tenia coli was less relative to the position in vascular smooth muscle.
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PMID:Changes of response to caffeine in Ca(2+)-deficient medium in guinea-pig tenia coli. 937 43


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