Inhibition of skeletal muscle sarcoplasmic reticulum CaATPase activity by calmidazolium.

Anderson, Kenneth W.; Coll, R J; Murphy, Alexander J.

doi:10.1016/s0021-9258(18)90887-2

Cited by 32 publications

(6 citation statements)

References 22 publications

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“…Calmidazolium chloride ( 7 ) is a positively charged and hydrophobic molecule that has been suggested to exert its biological effect by destabilising membrane phospholipids 55 rather than by being a calmodulin antagonist 56 . This compound was one of the most potent and selective anti- Trypanosoma molecule identified in the biological screening.…”

Section: Discussionmentioning

confidence: 99%

Drug-like molecules with anti-trypanothione synthetase activity identified by high throughput screening

Benítez

Franco

Sardi

et al. 2022

Journal of Enzyme Inhibition and Medicinal Chemistry

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Section: Discussionmentioning

confidence: 99%

Drug-like molecules with anti-trypanothione synthetase activity identified by high throughput screening

Benítez

Franco

Sardi

et al. 2022

Journal of Enzyme Inhibition and Medicinal Chemistry

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“…At high drug concentrations or low vesicle concentrations, the drugs become ineffective as diagnostic tools by rendering the membranes "leaky" to small solutes and ions such as [3H]sucrose and Ca2+. Partitioning of the drugs into the bilayer has been reported to cause alterations in SR membrane structure, thereby promoting Ca2+ efflux as well as inhibition of the (Ca2+ + Mg2+)-dependent ATPase of sarcoplasmic reticulum (Ho et al, 1983;Volpe et al, 1984;Anderson et al, 1984;Prokopjeva et al, 1984).…”

Section: Discussionmentioning

confidence: 99%

“…Abbreviations: SR, sarcoplasmic reticulum; EGTA, ethylene glycol bis(#3-aminoethyl ether)-/V,/V,Ñ',/V'-tetraacetic acid; AMP-PCP, adenosine 5'-(/3,7-methylenetriphosphate); Pipes, 1,4-piperazinediethanesulfonic acid; cAMP, adenosine cyclic 3',5'-phosphate. Other more indirect approaches involving the use of calmodulin inhibitors have been inconclusive in that these drugs seem to inhibit the ATPase in a reaction that is not mediated by calmodulin (Anderson et al, 1984;Prokopjeva et al, 1984). Tuana & MacLennan (1984) observed that two potent inhibitors of calmodulin, calmidazolium and compound 48/80, inhibit calmodulin-dependent protein phosphorylation and ATP-dependent Ca2+ uptake but not Ca2+-stimulated ATPase activity in skeletal muscle SR vesicles.…”

mentioning

confidence: 99%

Evidence of a role for calmodulin in the regulation of calcium release from skeletal muscle sarcoplasmic reticulum

Meissner¹

1986

Biochemistry

140

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The effect of calmodulin and calmodulin inhibitors on the "Ca2+ release channel" of "heavy" skeletal muscle sarcoplasmic reticulum (SR) vesicles was investigated. SR vesicles were passively loaded with 45Ca2+ in the presence of calmodulin and its inhibitors, followed by measurement of 45Ca2+ release rates by means of a rapid-quench-Millipore filtration method. Calmodulin at a concentration of 2-10 microM reduced 45Ca2+ efflux rates from passively loaded vesicles by a factor of 2-3 in media containing 10(-6)-10(-3) M Ca2+. At 10(-9) M Ca2+, calmodulin was without effect. 45Ca2+ release rates were varied 1000-fold (k1 approximately equal to 0.1-100 s-1) by using 10(-5) M Ca2+ with either Mg2+ or the ATP analogue adenosine 5'-(beta,gamma-methylenetriphosphate) in the release medium. In all instances, a similar 2-3-fold reduction in release rates was observed. At 10(-5) M Ca2+, 45Ca2+ release was half-maximally inhibited by about 2 X 10(-7) M calmodulin, and this inhibition was reversible. Heavy SR vesicle fractions contained 0.1-02 micrograms of endogenous calmodulin/mg of vesicle protein. However, the calmodulin inhibitors trifluoperazine, calmidazolium, and compound 48/80 were without significant effect on 45Ca2+ release at concentrations which inhibit calmodulin-mediated reactions in other systems. Studies with actively loaded vesicles also suggested that heavy SR vesicles contain a Ca2+ permeation system that is inhibited by calmodulin.

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“…Calmidazolium is a derivative of the antimycotic miconazole which is a potent inhibitor of calciumand calmodulin-dependent enzymes. It has been shown to inhibit the Ca2+-ATPase activity of sarcoplasmic reticulum in an uncompetitive manner, perhaps through an effect on membrane phospholipids (Anderson et al, 1984). We have used these two inhibitors to compare the catalytic cycles of the platelet and sarcoplasmic reticulum enzymes.…”

mentioning

confidence: 99%

An investigation of functional similarities between the sarcoplasmic reticulum and platelet calcium-dependent adenosinetriphosphatases with the inhibitors quercetin and calmidazolium

Fischer¹,

Campbell²,

White³

1987

Biochemistry

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The platelet and skeletal sarcoplasmic reticulum calcium-dependent adenosinetriphosphatases (Ca 2+ -ATPases) were functionally compared with respect to substrate activation by steady-state kinetic methods using the inhibitors quercetin and calmidazolium. Quercetin inhibited platelet and sarcoplasmic reticulum Ca 2+ -ATPase activities in a dose-dependent manner with IC 50 values of 25 and 10 µM, respectively. Calmidazolium also inhibited platelet and sarcoplasmic reticulum Ca 2+ -ATPase activities, with half-maximal inhibition measured at 5 and µM, respectively. Both inhibitors also affected the calcium transport acuity of intact platelet microsomes at concentrations similar to those which reduced Ca 2+ -ATPase activity. These inhibitors were then used to examine substrate ligation by the platelet and sarcoplasmic reticulum calcium pump proteins. For both Ca 2+ -ATPase proteins, quercetin has an affinity for the E-Ca 2 (fully ligated with respect calcium at the exterior high-affinity calcium binding sites, unligated with respect to ATP) conformational state of the protein that is approximately 10-fold greater than for other conformational states in the hydrolytic cycle. Quercetin can thus be considered a competitive inhibitor of the calcium pump proteins with respect to ATP. In contrast to the effect of quercetin, calmidazolium interacts with the platelet and sarcoplasmic reticulum Ca 2+ -ATPases in an uncompetitive manner. The dissociation constants for this inhibitor for the different conformational states of the calcium pump proteins were similar, indicating that calmidazolium has equal affinity for all of the reaction intermediates probed These observations indicate that the substrate ligation processes are similar for the two pump proteins. This supports the concept that the hydrolytic cycles of the two proteins are comparable.icrosomal fractions from human blood platelets transport calcium in an energy-dependent manner; Influx of calcium requires adenosine 5′-triphosphate (ATP), 1 is accompanied by the release of inorganic phosphate, is inhibited by agents that inhibit calcium-pumping Ca 2+

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Inhibition of skeletal muscle sarcoplasmic reticulum CaATPase activity by calmidazolium.

Cited by 32 publications

References 22 publications

Drug-like molecules with anti-trypanothione synthetase activity identified by high throughput screening

Drug-like molecules with anti-trypanothione synthetase activity identified by high throughput screening

Evidence of a role for calmodulin in the regulation of calcium release from skeletal muscle sarcoplasmic reticulum

An investigation of functional similarities between the sarcoplasmic reticulum and platelet calcium-dependent adenosinetriphosphatases with the inhibitors quercetin and calmidazolium

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