Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:4.6.1.1 (adenylate cyclase)
 19,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Histamine H2 receptor (H2R) has been shown to be coupled to adenylate cyclase. However, we have previously demonstrated that H2R-specific stimulation also activated phospholipase C in human HL-60 promyelocytic leukemia cells (Mitsuhashi M. et al. J. Biol. Chem. 264:18356, 1989). We have extended these studies on HL-60 cells to investigate whether histamine-bovine serum albumin conjugates (HA-BSA) specifically recognize H2R and activate phospholipase C pathways. Both histamine (HA) and HA-BSA increased intracellular concentrations of calcium in a H2R specific manner. However, HA-induced calcium mobilization was transient and returned to the basal level within 1-2 min, whereas HA-BSA-induced calcium mobilization was sustained for more than 10 min as a result of the additional influx of extracellular calcium. More interestingly, fluorescein (FITC) labeled HA-BSA was less incorporated into cytosols and present in the membrane fractions for more than 60 min, whereas membrane-bound FITC-HA was rapidly incorporated into cytosols. Furthermore, the levels of inositol 1,3,4,5-tetrakisphosphate, which is known to activate calcium channels were more sustained after HA-BSA stimulation than those of HA alone. These data suggest that H2R activation mechanism is more complex and may be modified by this slowly metabolized "compound ligand".
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PMID:Multiple signaling pathways of histamine H2 receptors. 190 5

Guanine nucleotide binding proteins (G proteins) are regulatory molecules that couple membrane receptors to effector systems such as adenylate cyclase and phospholipase C. The alpha subunits of G proteins bind to guanosine 5'-diphosphate (GDP) in the unstimulated state and guanosine 5' triphosphate (GTP) in the active state. Tiazofurin (2-beta-D-ribofuranosylthiazole-4-carboxamide), a specific inhibitor of inosine monophosphate (IMP) dehydrogenase, decreases guanylate synthesis from IMP in HL-60 promyelocytic leukemia cells and depletes intracellular guanine nucleotide pools. This study demonstrates that treatment of HL-60 cells with tiazofurin is associated with a fourfold increase in membrane binding sites for the nonhydrolyzable analogue GDP beta S. This increase in binding sites was associated with a 3.2-fold decrease in GDP beta S binding affinity. Similar findings were obtained with GTP gamma S. These effects of tiazofurin treatment on guanine nucleotide binding were also associated with decreased adenosine diphosphate-ribosylation of specific G protein substrates by cholera and pertussis toxin. The results further demonstrate that tiazofurin treatment results in inhibition of G protein-mediated transmembrane signaling mechanisms. In this regard, stimulation of adenylate cyclase by prostaglandin E2 was inhibited by over 50% in tiazofurin-treated cells. Furthermore, tiazofurin treatment resulted in inhibition of N-formylmethionylleucylphenylalanine-induced stimulation of phospholipase C. Taken together, these results indicate that tiazofurin acts at least in part by inhibiting the ability of G proteins to function as transducers of intracellular signals.
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PMID:Effects of tiazofurin on guanine nucleotide binding regulatory proteins in HL-60 cells. 196 38

The rat promyelocytic leukemia cell line BNML is highly sensitive to cAMP elevating agents, and to cholera toxin (CT) in particular: 99.9% of the cells are killed in less than 48 hr of toxin treatment. We described here a subclone of the same leukemia, which, in contrast, is completely resistant to CT but still sensitive to other cAMP inducers. This locates the defect responsible for CT resistance at the membrane, somewhere between surface CT receptors and adenylate cyclase. CT-resistant BNML cells (CTR-BNML) do have surface CT receptors (several thousands per cell). Adenylate cyclase activity in CTR-BNML cells is not stimulated by cholera toxin. Other GS mediated stimulation of adenylate cyclase (by PGE, isoproterenol, histamine, NaF) remains relatively high, though 25-60% lower than in CTS-BNML cells. These results suggest that a specific adenylate cyclase defect is involved in the resistance of CTR-BNML cells to cholera toxin.
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PMID:Cholera toxin resistance associated with deficient adenylate-cyclase activity in a subclone of the rat promyelocytic leukemia (BNML). 253 85

In order to analyze the complex activities of histamine H2 receptor activation on neutrophils, human HL-60 promyelocytic leukemia cells were differentiated into neutrophils by incubation with dimethyl sufoxide, loaded with the Ca2+-sensitive indicator dyes, indo-1 or fura-2, and the levels of intracellular Ca2+ ([Ca2+]i) measured in a fluorescent-activated cell sorter and fluorimeter, respectively. Histamine increased [Ca2+]i in a dose-dependent manner with a half-maximal concentration (EC50) of approximately 10(-6) to 10(-5) M, which exhibited H2 receptor specificity. Prostaglandin E2 and isoproterenol also induced [Ca2+]i mobilization in HL-60 cells, whereas the cell permeable form of cAMP and forskolin failed to increase [Ca2+]i. Since H2-receptor mediated [Ca2+]i mobilization was not inhibited by reducing the concentration of extracellular Ca2+ nor by the addition of Ca2+ channel antagonists, LaCl3 and nifedipine, [Ca2+]i mobilization is due to the release of Ca2+ from intracellular stores. Furthermore, both 10(-4) M histamine and 10(-6) M fMet-Leu-Phe increased the levels of 1,4,5-inositol trisphosphate. However, histamine-induced mobilization of [Ca2+]i was inhibited by cholera toxin but not by pertussis toxin, whereas the action of fMet-Leu-Phe was inhibited by pertussis toxin but not by cholera toxin. These data suggest that H2 receptors on HL-60 cells are coupled to two different cholera toxin-sensitive G-proteins and activate adenylate cyclase and phospholipase C simultaneously.
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PMID:Multiple signaling pathways of histamine H2 receptors. Identification of an H2 receptor-dependent Ca2+ mobilization pathway in human HL-60 promyelocytic leukemia cells. 255 5

Previously we identified a six-membered fragment 354TQVEHR359 of the C-terminal part of the PEDF (Pigment Epithelium-Derived Factor) differentiation factor molecule that shares homology with fragment 41TGENHR46 of the HLDF (Human Leukemia Differentiation Factor) differentiation factor molecule, which is responsible for its differentiation activity. HLDF has been isolated from the culture medium of human promyelocytic leukemia cell line HL-60. Hexapeptides HLDF-6 (TGENHR) and PEDF-6 (TQVEHR) corresponding to these HLDF and PEDF molecule fragments, which were previously shown to induce cell differentiation (Kostanyan et al. (2000) Russian Journal of Bioorganic Chemistry, 26, 505-511), also have neuroprotective properties. Both peptides prevent degeneration of Purkinje cells of rat cerebellar vermis upon chemical hypoxia induced by sodium azide in vivo; this effect is also observed on a behavioral level. Peptide HLDF-6 but not PEDF-6 promotes survival of HL-60 cells upon chemical hypoxia. Peptides HLDF-6 and PEDF-6 affect different second messenger biosynthesis systems in HL-60 cells. HLDF-6 diminishes cyclic AMP level in those cells due to adenylate cyclase inhibition, while PEDF-6 inhibits phosphatidylinositol-specific phospholipase C stimulated by aluminum tetrafluoride anions.
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PMID:Different mechanisms of protective and differentiative activities of homological peptides TGENHR and TQVEHR. 1537 65