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)

The effect of blockade of ouabain-sensitive alpha 2 and alpha 3 (neural type) isozymes of Na+, K(+)-ATPase was investigated on frog neuromuscular preparations by recording the frequency augmentation-potentiation (FAP) of the endplate potential, an electrophysiological and neuropharmacological technique to analyze the drug actions on the release process of the readily releasable transmitter quanta. Erythrosin B, which was thought to selectively inhibit the neural type Na+, K(+)-ATPase, pivoted the log-linear FAP relation counterclockwise without altering the intercept on the ordinate. Chlormadinone had a similar action. An increase in the concentration of extracellular K+ ions pivoted the FAP relation clockwise with a concomitant upward shift of the intercept on the ordinate, and low K+ Ringer's solution produced an inverse effect. In contrast, Li+ ions shifted the FAP relation upwards dose-dependently leaving its slope unchanged. Cinnarizine, a blocker for inositol-1,4,5-trisphosphate-induced Ca2+ release, and 5,5'-dimethyl-1,2-bis(2-amino-phenoxy)ethane-N,N,N',N'-tetraacetic acid, a specific intracellular Ca2+ chelator, significantly antagonized the potentiating action of Li+. The ouabain-sensitive neural type Na+, K(+)-ATPase isozyme, which is abundant in neural tissues, seems to play an important role in stimulation frequency-dependent modulation of the quantal transmitter release such as FAP.
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PMID:Effects of inhibitors of ouabain-sensitive Na+, K(+)-ATPase and Li+ ions on the neuromuscular transmission of the frog. 747 24

Cinnarizine (1-diphenylmethyl-4-(3-phenyl-2-propenyl)piperazine) and its di-fluorinated derivative flunarizine inhibit the MgATP-dependent generation of a transmembrane proton electrochemical gradient in chromaffin granule ghosts. The concentrations giving 50% inhibition (IC50) of the MgATP-dependent generation of the pH-gradient were 5.9+/-0.6 microM (n = 6) and 3.0+/-0.3 microM (n = 5) for cinnarizine and flunarizine, respectively. The IC50 values for inhibiting the generation of the membrane potential were even lower, i.e. 0.19+/-0.06 microM (n = 6) and 0.15+/-0.01 microM (n = 4) for cinnarizine and flunarizine, respectively. Cinnarizine (10 microM) also inhibited the energy-dependent vesicular uptake of [14C]-dopamine (50 microM) by 76%, i.e. from 2.1+/-0.9 to 0.5+/-0.6 nmol/mg protein/min (n = 5, P < 0.002). Cinnarizine (10 microM) increased the MgATPase activity of the granule ghosts by 47+/-26% (n = 4) compatible with an uncoupling of the vacuolar H+-ATPase activity. The IC50-values observed for the two compounds are in the same range as their reported therapeutic plasma concentrations in vivo, suggesting that cinnarizine and flunarizine may well inhibit proton pumping and catecholamine uptake in storage vesicles also in vivo. This mechanism of action may contribute to the drug-induced parkinsonism seen as a side-effect of the two drugs.
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PMID:Drug-induced parkinsonism: cinnarizine and flunarizine are potent uncouplers of the vacuolar H+-ATPase in catecholamine storage vesicles. 1046 91