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At least 19 recordsLinked to original sources
PubMed1996

Action of 5-hydroxytryptamine in facilitating N-methyl-D-aspartate depolarization of cortical neurones mimicked by calcimycin, cyclopiazonic acid and thapsigargin.

1. The ability of calcimycin, cyclopiazonic acid and thapsigargin to facilitate the N-methyl-D-aspartate (NMDA)-mediated depolarization of cortical projection neurones was investigated by use of grease-gap recording and the results compared with the facilitation that results from activation of 5-hydroxytryptamine2A receptors. 2. Calcimycin (0.25 to 3 microM), cyclopiazonic acid (5 to 30 microM), and thapsigargin (10 to 300 nM) reversibly facilitated the NMDA (50 microM)-induced depolarization in the presence of tetrodotoxin. The concentration-response relationships were bell-shaped with a mean enhancement of 550% for calcimycin (1 microM) and approximately 400% for cyclopiazonic acid (20 microM) and thapsigargin (100 nM). At the highest concentration of each agent tested, no facilitation was observed. 3. Chlorpromazine (1 microM) partially restored a facilitation at 3 microM calcimycin and 300 nM thapsigargin. Myo-inositol (10 mM) and 100 nM staurosporine were both ineffective in this regard. 4. The depolarization elicited by 10 microM quisqualate or 5 microM kainate was not facilitated by 10 microM cyclopiazonic acid. 5. Calcimycin (0.5 microM), cyclopiazonic acid (20 microM), and thapsigargin (100 nM) elicited a significant facilitation in the presence of an antagonist cocktail consisting of D,L-2-amino-3-phosphonopropionic acid, prazosin, ritanserin, and scopolamine, although the magnitude of the facilitation was reduced. 6. Facilitation of the NMDA depolarization elicited by both 30 microM 5-hydroxytryptamine and 10 microM phenylephrine was eliminated in nominally Mg(2+)-free medium. In contrast, the facilitation induced by 0.5 microM calcimycin remained intact. 7. Bis-(o-aminophenoxy)-ethane-N,N,N,N, tetraacetic acid aminoethoxy (50 microM) or perfusion with nominally Ca(2+)-free medium eliminated facilitation of the NMDA depolarization induced by 30 microM 5-hydroxytryptamine and 100 nM thapsigargin. 8. The facilitation induced by both 30 microM 5-hydroxytryptamine and 1 microM calcimycin was reduced in a concentration-dependent manner by nifedipine (1 to 10 microM). 9. Calcimycin, cyclopiazonic acid and thapsigargin facilitate the NMDA depolarization in a manner which closely mimics the facilitation induced by 5-hydroxytryptamine. It is concluded that enhancement of the NMDA depolarization at cortical projection neurones results from an elevation of Ca2+ in the cytosol and that several sources of Ca2+ contribute to the facilitation.

Animals↗
PubMed1990

Kinetic properties of cation/H(+)-exchange: calcimycin (A23187)-mediated Ca2+/2H(+)-exchange on the bilayer lipid membrane.

The calcimycin (A23187)-mediated electrically silent flux of hydrogen ions coupled with a counter transport of calcium or magnesium ions was measured by the method of local pH changes recording in the unstirred layers near the planar bilayer lipid membrane (BLM). It was shown that: (1) the pH dependence of calcimycin-mediated Ca2+/2H+ exchange had a maximum at pH 7; (2) the apparent Michaelis constant for the alkali earth cations were higher at acidic pH than the corresponding values at alkaline pH; (3) the apparent Michaelis constant for calcium was similar to that for magnesium ions in agreement with calcimycine cation binding constants; (4) the ratio of calcium and magnesium fluxes was independent of pH in the pH range from 5 to 8. (5) the flux was proportional to the calcimycin concentration at pH greater than 6.3 and proportional to the square of the carrier concentration at pH less than 5; (6) the addition of calcium ion chelator EDTA increased the flux significantly. These data were discussed in terms of the model of cation/H(+)-exchange and it was concluded that the dissociation of the cation-carrier complex at the membrane/water interface played an important role in the process of calcimycine operation. The comparison of the kinetic properties of calcimycin with the previously described kinetics of nigericin (Antonenko and Yaguzhinsky (1988) Biol. Membr. (Russian) 5, 718-728) revealed much similarity. On the other hand, a significant difference was found between the mechanism of the nigericin K/Na selectivity and calcimycin Ca/Mg selectivity.

Binding, Competitive↗
PubMed1998

Effect of Bay K 8644, calcimycin and phorbol ester on radiation-induced decreases in the release of norepinephrine in the hippocampus in rats.

Gamma radiation (10 Gy at 10 Gy/min from a 60Co source) induces a decrease in the release of norepinephrine in the hippocampus 48 h after exposure. The purpose of this study was to determine the effect of Bay K 8644 [methyl-1,4-dihydro-2,6-dimethyl-3-nitro-4-2(trifluoromethylphenyl)py rid ine-5-carboxylate], an agonist for L- and N-type calcium channel subtypes; calcimycin [6S-[6alpha(2S*,3S*),8beta(R*),9beta,11alpha]-5( methylamino)-2-[[3,9,11-trimethyl-8-[1-methyl-2-oxo-2(1H-pyrrol-2-yl)eth yl]-1,7-dioxaspiro[5,5]undec-2-yl]methyl]-4-benzoxazoleca rboxylic acid], a calcium ionophore which increases intracellular Ca2+; and phorbol 12-O-tetradecanoate 13-acetate (TPA), which stimulates protein kinase C (PKC) alone or in combination with decreases in the release of norepinephrine in the hippocampus 48 h after irradiation. Neither Bay K 8644 (1-100 nM), calcimycin nor TPA prevented the radiation-induced decreases in the release of norepinephrine in the hippocampus. However, 10 nM of Bay K 8644 or calcimycin in combination with 1-100 nM of TPA or 10 nM of TPA in combination with 1-100 nM of Bay K 8644 or calcimycin did prevent the radiation-induced decreases in the release of norepinephrine. These results suggest that stimulation of PKC by TPA and mobilization of calcium by Bay K 8644 or calcimycin are necessary to prevent the radiation-induced decreases in the release of norepinephrine in the hippocampus.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1995

Calcimycin-induced lens epithelial cell apoptosis contributes to cataract formation.

Previous studies have shown that calcimycin induces cataract in organ culture. To investigate the mechanism of this induction, the viability of lens epithelial cells in calcimycin (calcium ionophore, A23187)-treated rat lenses were examined. During incubation of lenses with 5 microM calcimycin, apoptotic epithelial cells were found after a 2-hr treatment as determined by terminal deoxynucleotidyl transferase (TdT) labeling. The percentage of apoptotic cells quickly rose as the incubation time increased. After a 12-hr incubation, more than 60% of the lens epithelial cells underwent apoptosis. Prolonged c-fos expression, previously shown to be an indicator of programmed cell death, was also observed during this treatment. DNA fragmentation assays further confirmed that the TdT labeled cells were indeed apoptotic. Under the same incubation conditions, the cultured lenses gradually lost transparency and became completely opaque in about 30 hr. Since the vertebrate lens contains only a single layer of epithelial cells, apoptotic death of these cells activated by calcimycin quickly destroys the lens epithelium, impairs homeostasis of the underlying fiber cells and initiates development of lens opacification.

Animals↗
PubMed1994

[Effects of calcimycin on platelet adhesion to cultured bovine cerebral microvascular endothelial cells and its antagonism by drugs].

Calcimycin induced rabbit platelet adhesion to cultured bovine cerebral microvascular endothelial cells (CMEC) and its inhibition by triazelodiazepine (WEB 2086), 1,5-bis-(3,4-dimethoxyphenyl)-tetrahydro-(4H)-pyran (DMPP) and tetrandrine (Tet) were investigated. The results showed that calcimycin significantly increased platelet adhesion to CMEC. The platelet adhesion to CMEC was increased by 17.1% vs control after stimulation with calcimycin 0.01 mumol.L-1 for 25 min. WEB 2086 0.1, 1.0 and 10.0 mumol.L-1 or DMPP 0.1, 1.0 and 10.0 mumol.L-1 or Tet 0.1, 1.0 and 10.0 mumol.L-1 inhibited the calcimycin induced platelet adhesion to CMEC by 9.0, 22.9 and 23.1% or 9.7, 15.6 and 22.1% or 7.8, 15.6 and 24.6%, respectively. This indicates that DMPP and Tet may have perspectives in the prevention and treatment of cerebral vascular diseases.

Alkaloids↗
PubMed1990

[Inhibitory effect of dauricine on platelet activating factor released from calcimycin-induced mouse peritoneal macrophages].

The effects of dauricine (Dau) on the release of platelet activating factor (PAF) from mouse peritoneal macrophages stimulated by calcimycin (A-23187) was studied. The method of sodium [3H]acetate incorporating into macrophages to synthesize PAF was set up for the first time. Calcimycin (0.2 mumol/L) significantly induced mouse peritoneal macrophages to utilize sodium [3H]acetate to synthesize PAF. PAF released from macrophages medium fluid increased as the concentration of sodium [3H]acetate increased. The maximal amount of PAF released from macrophages was attained by incubating macrophages with sodium [3H]acetate (250 mumol/L) and calcimycin (2 mumol/L) over 30 min. Extracted by CHCl3:CH3OH:H2O (2:2:1.8), separated by thin layer chromatography (TLC) and determined by liquid scintillation counting, PAF released was inhibited significantly by Dau both in time (10-30 min) and dose (1-1000 mumol/L) dependent manners. The IC50 of Dau for the formation of PAF was 2.5 mumol/L. On the same condition PAF release was also significantly inhibited by quinacrine at 500 mumol/L. The results indicate that Dau is a potent inhibitor of PAF synthesis in mouse peritoneal macrophages.

Alkaloids↗
PubMed1991

Calcimycin potentiates responses of rat hippocampal neurons to N-methyl-D-aspartate.

We examined the effect of elevating intracellular calcium ([Ca2+]i) on responses to iontophoretically applied N-methyl-D-aspartate (NMDA), and quisqualate in CA1 neurons of the hippocampal slice. Topical application of calcimycin (A23187), a calcium ionophore, potentiated responses to NMDA but not to quisqualate. This potentiation was prevented by loading cells with the calcium chelator, BAPTA, suggesting that the action of calcimycin on NMDA receptors was mediated by an elevation of [Ca2+]i in the recorded cell. The potentiation was also recorded in voltage-clamped and in cesium-loaded cells, suggesting that it was not mediated by non-specific changes in voltage or input resistance of the cell that may have resulted from the rise in [Ca2+]i. We propose that intracellular calcium plays a crucial role in regulating the activity of the NMDA subtype of L-glutamate receptor.

Animals↗
PubMed1992

Inhibition of calcimycin-induced stimulation of cytosolic calcium in human PMN by a LTB4 receptor antagonist.

This study investigates the significance of PMN-derived LTB4 for PMN activation by using a selective LTB4 antagonist (SC 41930). Human PMN were stimulated by platelet-activating-factor (PAF, 3 microM), a receptor dependent agonist, or by calcimycin (A 23187, 10 microM), a receptor independent agonist. PMN activation was determined by LTB4 release and changes in free cytosolic Ca++ levels. Pretreatment of the PMN with SC 41930 (0.1-10 microM) caused a concentration-dependent inhibition of agonist induced rise in cytosolic Ca++ with both PAF and calcimycin. Interestingly, at the same concentrations of SC 41.930, there was a concentration-dependent inhibition of LTB4 release. Control experiments with a cell-free 5-lipoxygenase preparation did not show any direct effect of SC 41930 on the enzyme under conditions when nordihydroguiaretic acid was active. The data demonstrate a nonselective inhibition of agonist induced PMN activation by the LTB4 receptor antagonist SC 41930 and suggest that formation of endogenous LTB4 is involved in a positive feed-back loop that is required for maximum stimulation of PMN function even by a calcium ionophore.

Arachidonate 5-Lipoxygenase↗
PubMed1991

Effects of gossypol on phorbol ester-calcimycin-induced prostaglandin synthesis by macrophages.

Arachidonic acid metabolism via cyclooxygenase pathway in mouse resident peritoneal macrophages were stimulated by phorbol-12-myristate-13-acetate (PMA), calcimycin and exogenous arachidonic acid, respectively. Racemic, (-) and (+)-gossypol dose-dependently inhibited PMA or calcimycin-induced synthesis of prostacyclin, thromboxane A2 and prostaglandin F2 alpha, but failed to affect arachidonic acid-induced synthesis of prostaglandin. It is suggested that both (-)-gossypol and (+)-gossypol inhibit synthesis of prostaglandin at the level of arachidonic acid release, and the inhibition of prostaglandin synthesis by gossypol might not be the main mode of its antifertility action.

6-Ketoprostaglandin F1 alpha↗
PubMed1986

Semi-synthesis of A23187 (calcimycin) analogs. III. Modification of benzoxazole ring substituents, ionophorous properties in an organic phase.

Ten semi-synthetic analogs of A23187 (calcimycin), with only the benzoxazole ring substituents modified together with the ionophore X14885A were studied with regard to their calcium and magnesium carrier properties through an organic phase (toluene - butanol, 70:30). The results indicate that the carboxylic group and the oxazolic nitrogen, maintained in the ortho position are essential for the ionophorous properties. Further, the introduction of a substituent in place of the NHCH3 group, producing steric hindrance of the carboxylic group leads to a destabilization of the 2:1 associations with cations.

Benzoxazoles↗
PubMed1991

[Inhibitory effect of esculentoside A on platelet activating factor released from calcimycin induced rat peritoneal macrophages].

Platelet activating factor (PAF) is a kind of inflammatory mediator. We used the method of aggregation of washed rabbit platelet to study the effect of esculentoside A (EsA) on the release of PAF from calcimycin (A23187)stimulated rat peritoneal macrophages and found that the release of PAF was inhibited by EsA in a time and dose dependent manner. The IC50 of EsA for the inhibition of PAF release was 1.5 mumol/L. Under the same condition, the release of PAF was also inhibited by mepacrine at 100 mumol/L. The results indicate that EsA is a potent inhibitor of PAF synthesis in rat peritoneal macrophages.

Animals↗
PubMed1996

Effects of egtazic acid and calcimycin on synthesis of DNA and collagen in cultured human lung fibroblasts.

AIM: To study the effects of egtazic acid (EA) and calcimycin (Cal) on the synthesis of DNA and collagen in cultured human lung fibroblasts (HLF). METHODS: The synthesis of DNA and collagen was determined by measuring the incorporation of [3H]TdR and [3H]proline of HLF respectively. RESULTS: The collagen synthesis increased markedly 24 h after exposure to both EA (0.05-4 mmol.L-1) and Cal (0.25-20 mumol.L-1), and that there was no obvious change in DNA synthesis. After 36-48-h exposure, both DNA and collagen syntheses decreased in the groups of EA (1, 2, and 4 mmol.L-1); the DNA synthesis was also suppressed in Cal groups in a concentration-dependent manner, whereas collagen synthesis decreased only in Cal (10 and 20 mumol.L-1). CONCLUSION: Extracellular Ca2+ influx into fibroblasts increased collagen production, However, the DNA synthesis was suppressed when the cytosolic Ca2+ was too high or too low.

Biological Transport, Active↗
PubMed1991

[Effects of econazole and clotrimazole on TXB2 and PGE2 production in calcimycin-stimulated neutrophils and arachidonic acid-stimulated platelets].

The effects of econazole and clotrimazole which are used as antifungal agents, on TXB2 and PGE2 production in calcimycin (A-23187)-stimulated rat pleural neutrophils and arachidonic acid (AA)-stimulated washing rabbit platelets were examined by radioimmunoassay. Econazole and clotrimazole 0.05-100 mumol.L-1 inhibited TXB2 production both in rat pleural neutrophils and in rabbit platelets with a dose-dependent manner. The most potent inhibition was found in rabbit platelets. At the concentration of 50 mumol.L-1, econazole and clotrimazole were sufficient to inhibit TXB2 production in rabbit platelets by up to 99% and 98% respectively. Econazole and clotrimazole 0.05-5 mumol.L-1 also increased PGE2 biosynthesis in rabbit platelets. But econazole and clotrimazole 50 mumol.L-1 reduced the PGE2 production in rabbit platelets to 11% and 37% of the amounts of 5 mumol.L-1 econazole and clotrimazole respectively. The results suggest that econazole and clotrimazole at lower concentration may have a selective inhibitory effect on thromboxane synthetase, at higher concentration they also inhibit cyclooxygenase.

Animals↗
PubMed1992

A radioautographic study of [3H]-A 23187 (calcimycin) in components of the brain. Distribution in different cell types of the diencephalo-mesencephalic roof.

The distribution of the ionophore [3H]-A 23187 was examined by means of light and electron microscopy in elements of the central nervous system located in the diencephalo-mesencephalic roof. A 23187 is not evenly distributed in the components studied (ependyma, secretory ependyma of the subcommissural organ and neurons of the mesencephalon). At the cellular level, A 23187 appears preferentially associated with the cytoplasmic membrane as well as with the internal membranous system.

Animals↗
PubMed1989

[Inhibition of release of prostaglandins and leukotrienes from calcimycin-induced mouse peritoneal macrophages and bovine aorta endothelial cells by anisodamine].

[3H]Arachidonic acid (AA)-prelabeled mouse peritoneal macrophages were stimulated by calcium ionophore A-23187 to release [3H]AA metabolites. The major labeled products which were co-chromatographed with the authentic PG and LT standards by TLC and determined by liquid scintillation were 6-keto-PGF1 alpha, PGE2, LTC4, and LTB4. Anisodamine (Ani) significantly inhibited the A-23187-induced release of PG and LT from mouse macrophages in a dose-dependent manner. In the presence of Ani at 0.5 mmol/L, the A-23187-induced release of 6-keto-PGF1 alpha, PGE2, LTC4 and LTB4 was reduced by 57%, 20%, 53% and 49%, respectively. A-23187-induced release of 6-keto-PGF1 alpha measured by RIA from bovine aorta endothelial cells was also significantly inhibited by Ani in a dose-dependent manner. These results indicate that the calcium-antagonistic effects of Ani may not only play a significant role in its inhibiting release of PG and LT, but also contribute to its salutary effects in the treatment of septic shock.

6-Ketoprostaglandin F1 alpha↗
PubMed2005

Calcium-activated RAF/MEK/ERK signaling pathway mediates p53-dependent apoptosis and is abrogated by alpha B-crystallin through inhibition of RAS activation.

The ocular lens is the only organ that does not develop spontaneous tumor. The molecular mechanism for this phenomenon remains unknown. Through examination of the signaling pathways mediating stress-induced apoptosis, here we presented evidence to show that different from most other tissues in which the extracellular signal-regulated kinases (ERKs) pathway is generally implicated in mediation of survival signals activated by different factors, the RAF/MEK/ERK signaling pathway alone plays a key role in stress-activated apoptosis of lens epithelial cells. Treatment of N/N1003A cells with calcimycin, a calcium mobilizer, activates the RAF/MEK/ERK pathway through RAS, which is indispensable for the induced apoptosis because inhibition of this pathway by either pharmacological drug or dominant negative mutants greatly attenuates the induced apoptosis. Calcimycin also activates p38 kinase and JNK2, which are not involved in calcium-induced apoptosis. Downstream of ERK activation, p53 is essential. Activation of RAF/MEK/ERK pathway by calcimycin leads to distinct up-regulation of p53. Moreover, overexpression of p53 enhances calcimycin-induced apoptosis, whereas inhibition of p53 expression attenuates calcimycin-induced apoptosis. Up-regulation of p53 directly promotes Bax expression, which changes the integrity of mitochondria, leading to release of cytochrome c, activation of caspase-3 and eventually execution of apoptosis. Overexpression of alphaB-crystallin, a member of the small heat-shock protein family, blocks activation of RAS to inhibit ERK1/2 activation, and greatly attenuates calcimycin-induced apoptosis. Together, our results provide 1) a partial explanation for the lack of spontaneous tumor in the lens, 2) a novel signaling pathway for calcium-induced apoptosis, and 3) a novel antiapoptotic mechanism for alphaB-crystallin.

Animals↗