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  • 1
    Electronic Resource
    Electronic Resource
    Bovine adrenal cortex adenylate cyclase: Properties of the particulate enzyme and effects of guanyl nucleotides (1975)
    Springer
    Naunyn-Schmiedeberg's archives of pharmacology 289 (1975), S. 77-97 
    Details
    ISSN: 1432-1912
    Keywords: ACTH ; Adenylate Cyclase ; Guanyl Nucleotide Sites ; 5′-Guanylyl-Imidodiphosphate
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The preparation of a partially purified plasma membrane fraction from bovine adrenal cortex is described. Adenylate cyclase in this particulate preparation retained high sensitivity to ACTH and is also stimulated by 5′-guanylyl-imidodiphosphate [Gpp(NH)p]. GTP, in contrast to Gpp(NH)p, had very little intrinsic activity to stimulate adenylate cyclase. GTP could however, with high affinity, inhibit the Gpp(NH)p effects on adenylate cyclase. When the concentration of creatine phosphate, a component of the ATP-regenerating system in the adenylate cyclase assay mixture, was lowered from 20 to 2 mM (at 0.1 mM ATP, 5 mM Mg2+) GTP, dGTP and other nucleotides like ITP and much less UTP or CTP gained considerable intrinsic activity in the presence of ACTH to stimulate adenylate cyclase. The apparent affinities of the nucleotides for ACTH-stimulated adenylate cyclase from bovine adrenal cortex (at 2 mM creatine phosphate) were, GTP=dGTP〉Gpp(NH)p〉Gpp(CH2)p (5′-guanylyl-β, γ-methylene-diphosphonate) 〉ITP〉UTP〉CTP. These findings indicate that regulatory nucleotide binding sites exist for bovine adrenal cortex adenylate cyclase. Their specificity is similar to the nucleotide sites modulating angiotensin binding in bovine adrenal cortex plasma membranes (Glossmann et al., 1974a). The regulatory nucleotide binding sites for the adrenal cortex adenylate cyclase complex can also be identified under conditions where only Gpp(NH)p has high intrinsic activity (e.g. at 20 mM creatine phosphate) but other nucleotides like GTP act as antagonists. Both stimulants, ACTH and Gpp(NH)p, appear to remain firmly bound to the particulate membrane preparation, as suggested by preincubation experiments.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00498031
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  • 2
    Electronic Resource
    Electronic Resource
    Purification of the putative calcium channel from skeletal muscle with the aid of [3H]-nimodipine binding (1983)
    Springer
    Naunyn-Schmiedeberg's archives of pharmacology 323 (1983), S. 1-11 
    Details
    ISSN: 1432-1912
    Keywords: Skeletal muscle ; Calcium channel blocker ; [3H]-Nimodipine ; Isolation
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary High affinity (K D=1.5 nmol/l) binding sites for the potent 1.4-dihydropyridine calcium channel blocker [3H]-nimodipine have been found in guinea-pig skeletal muscle homogenates. These sites could be enriched by differential centrifugation in a crude microsomal fraction. In the microsomal fraction the density of binding sites was 2pMol per mg of protein. The pharmacological profile of the [3H]-nimodipine binding sites suggests that they are part of the putative calcium channel and that [3H]-nimodipine binding can be used as a marker for these ionic pores. In guinea-pig brain membranes [3H]-nimodipine labels a single class of sites with a K D of 0.6 nmol/l and d-cis-diltiazem decreases the K D by a factor of three without a change in the maximum number of receptors. In contrast d-cis-diltiazem (at the optimal concentration of 10 μmol/l) increases the density of the sites in guinea-pig skeletal muscle available for [3H]-nimodipine with high affinity and the K D decreases marginally to 1.0 nmol/l. These effects of d-cis-diltiazem are stereospecific since the pharmacologically inactive diastereoisomer l-cis-diltiazem does not stimulate [3H]-nimodipine binding, but is inhibitory, albeit at much higher concentrations. It is concluded that a significant fraction of the putative calcium channels has a K D of 〉50 nmol/l for [3H]-nimodipine, and that d-cis-diltiazem can increase the affinity of this subpopulation for [3H]-nimodipine so that they are detectable in ligand binding experiments. The binding sites of [3H]-nimodipine have been purified from the crude microsomal pellet by means of sucrose gradient centrifugation. [3H]-nimodipine binding copurifies with (Na+, K+)-ATP' ase and [3H]-ouabain binding and is enriched in a vesicular fraction (by a factor of 30–60 fold) of low bouyant density [〈25% (w/w) sucrose], with a ratio of (Na+, K+)-ATP'ase to Ca2+-ATP'ase activity of 0.77. Biochemical and electron microscopic examination suggests that a specialized structure of the sarcolemma, possibly the transverse tubule, is the subcellular locus for the [3H]-nimodipine binding site. Since the density of the drug receptors in this purified preparation is extremely high and exceeds that reported for [3H]-saxitoxin binding sites (a specific sodium channel label) by a factor of 4–10 (with respect to most highly purified skeletal muscle membrane isolated), the isolation and purification of the putative calcium channel from skeletal muscle is feasable. Our results confirm recent findings with biophysical methods, on the presence of calcium channels which are blocked by (±) D-600, d-cis-diltiazem and the 1,4-dihydropyridine nifedipine in skeletal muscle. The data are discussed in the context of the possible physiological role of calcium channels located in transverse tubules.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00498821
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  • 3
    Electronic Resource
    Electronic Resource
    [3H]HOE166 defines a novel calcium antagonist drug receptor — distinct from the 1,4 dihydropyridine binding domain (1989)
    Springer
    Naunyn-Schmiedeberg's archives of pharmacology 340 (1989), S. 752-759 
    Details
    ISSN: 1432-1912
    Keywords: Benzothiazinones ; Purified calcium channels ; Drosophila ; Calcium channel blockers ; Skeletal muscle
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Benzothiazinones represent a novel class of drugs which block voltage-dependent L-type calcium channels in different tissues. [3H]HOE166 (R-(±)-3,4-dihydro-2-isopro-opyl-4-methyl-2-[2-[4-[4-[2-(3, 4, 5-trimethoxyphenyl)ethyl]piperazinyl]butoxy]phenyl]-2H -1, 4-benzothiazin-3-on-dihydrochloride; ≈ 57 Ci/mmol) a potent optically pure benzothiazinone was employed to characterize receptors associated with skeletal muscle transverse tubule calcium channels. [3H]HOE166 reversibly labels the membrane-bound calcium channels with high affinity (Kd = 0.36 ± 0.05 nM; Bmax = 18.2 ± 3.3 pmol/mg of membrane protein; means ± SD, n = 13), HOE166 (Ki = 0.76 nM) is 29-fold more potent than the respective (S)-enantiomer (Ki = 22.1 nM). Binding is inhibited by divalent and trivalent cations (Cd2+ and La3+ being most potent) and other calcium channel drugs (1,4 dihydropyridines, phenylalkylamines, benzothiazepines). High affinity [3H]HOE166 binding activity is maintained (Kd = 4.5–9.0 nM) after solubilization and purification (554–1350 pmoles/mg of protein) of the calcium channel complex from transverse-tubule membranes. The following data support our recent claim (Striessnig et al. 1985, 1988) that HOE166 labels a domain on L-type calcium channels which is distinct from that defined by 1,4 dihydropyridines, phenylalkylamines or benzothiazepines: (1) All 1,4 dihydropyridine-, phenylalkylamine-and benzothiazepine-receptor-selective drugs tested are only very weak inhibitors of [3H]HOE166 binding. (2) (+)-PN200-110 only partially inhibits [3H]HOE166 binding to the purified calcium. channel complex. (3) The decay of the [3H]HOE166-receptor complex is monoexponential but the dissociation rate constants depend on the ligand concentration; (+)-PN200-100 accelerates the dissociation in the presence of unlabelled HOE166. (4) Nanomolar concentrations of HOE166 and HOE167 completely inhibit (−)-[3H]desmethoxyverapamil binding to a Drosophila phenylalkylamine receptor (which lacks a 1,4 dihydropyridine binding domain). Taken together, these results are incompatible with the view that [3H]HOE166 binds competitively to the calcium channel linked 1,4 dihydropyridine drug receptors.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00169685
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  • 4
    Electronic Resource
    Electronic Resource
    Differential labelling of putative skeletal muscle calcium channels by [3H]-nifedipine, [3H]-nitrendipine, [3H]-nimodipine and [3H]-PN 200 110 (1983)
    Springer
    Naunyn-Schmiedeberg's archives of pharmacology 323 (1983), S. 276-277 
    Details
    ISSN: 1432-1912
    Keywords: Calcium channel blocker ; Radioligand ; Differential labelling ; Skeletal muscle
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Four 1,4-dihydropyridine calcium channel blockers [3H]-nifedipine, [3H]-nitrendipine, [3H]-nimodipine and [3H]-PN 200 110 (Isopropyl 4-(2,1,3,benzoxadiazol-4-yl)-1,4-dihydro-2,6-dimethyl-5-methoxy-carbonylpyridine-3-carboxylate) were employed to label putative calcium channels in guinea-pig hind limb skeletal muscle membranes. The four radioligands differed with respect to the number of sites (B max) which were labelled. The following rank order of B max values was found: PN 200 110 〉 nimodipine = nitrendipine 〉 nifedipine. d-cis-Diltiazem caused an increase in the density of high-affinity binding sites for all four calcium channel blockers. The relative stimulation was smallest for PN 200 110. It is suggested that 1,4-dihydropyridines exhibit different efficacies for induction of a channel state with high affinity for these drugs.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00497674
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