neuropeptide-y and Leukemia--Erythroblastic--Acute

neuropeptide-y has been researched along with Leukemia--Erythroblastic--Acute* in 11 studies

Other Studies

11 other study(ies) available for neuropeptide-y and Leukemia--Erythroblastic--Acute

ArticleYear
Structure-activity relationships of neuropeptide Y Y1 receptor antagonists related to BIBP 3226.
    Bioorganic & medicinal chemistry letters, 2000, Jul-17, Volume: 10, Issue:14

    Analogues of BIBP 3226, (R)-N(alpha)-diphenylacetyl-N-(4-hydroxybenzyl)argininamide, were synthesized and investigated for Y1 antagonism (Ca2+-assay, HEL cells) and binding on Y1, Y2 and Y5 receptors. Replacing the benzylamino by a tetrahydrobenzazepinyl group preserves most of the Y1 activity. Combination with a N(G)-phenylpropyl arginine and a N(alpha)-p-biphenylylacetyl moiety shifted the NPY receptor selectivity towards Y5.

    Topics: Animals; Arginine; Drug Design; Humans; Kinetics; Leukemia, Erythroblastic, Acute; Molecular Conformation; Molecular Structure; Neuropeptide Y; Receptors, Neuropeptide Y; Structure-Activity Relationship; Swine; Tumor Cells, Cultured

2000
Neuropeptide-Y stimulation of extracellular signal-regulated kinases in human erythroleukemia cells.
    The Journal of pharmacology and experimental therapeutics, 1999, Volume: 291, Issue:3

    We have used human erythroleukemia (HEL) cells to investigate distal signaling mechanisms of neuropeptide-Y (NPY) receptors. NPY did not activate phospholipase D, determined as a phosphatidylethanol formation, or protein kinase C (PKC) determined enzymatically as a translocation to the plasma membrane. However, NPY caused a rapid (already maximal after 30 s) and concentration-dependent (maximum at 10-100 nM) activation of extracellular signal-regulated kinase (ERK) as assessed by immunoblotting with epitope-specific, antiphosphotyrosine antibodies and in some cases enzymatically. ERK activation by 100 nM NPY was abolished by the Y(1) NPY receptor antagonist BIBP 3226 (1 microM), pertussis toxin treatment (100 ng ml(-1) overnight), the mitogen-activated protein kinase (MAPK) kinase inhibitor PD 98059 (100 microM), and the phosphatidylinositol-3-kinase inhibitor wortmannin (100 nM). Whereas the PKC inhibitor staurosporine (3 microM) inhibited ERK activation by NPY, the chemically distinct PKC inhibitors calphostin C (3 microM), Gö 6976 (3 microM), and bisindolylmaleimide I (3 microM) did not. NPY did not activate other MAPK such as jun N-terminal kinase or p38 MAPK. We conclude that NPY does not activate phospholipase D, PKC, jun N-terminal kinase, or p38 MAPK in HEL cells. However, NPY activates ERK by a pathway involving Y(1) receptors, pertussis toxin-sensitive G proteins, and phosphatidylinositol-3-kinase, whereas PKC may not be involved. Staurosporine may have PKC-independent effects on ERK activation.

    Topics: Enzyme Inhibitors; Extracellular Space; Humans; Leukemia, Erythroblastic, Acute; Mitogen-Activated Protein Kinases; Neuropeptide Y; Phospholipase D; Phosphotransferases; Protein Kinase C; Signal Transduction; Stimulation, Chemical; Tumor Cells, Cultured

1999
Antagonistic properties of centrally truncated analogs of [D-Trp(32)]NPY.
    Journal of medicinal chemistry, 1996, Mar-01, Volume: 39, Issue:5

    We have previously shown that [D-Trp(32)]NPY can competitively antagonize NPY-induced feeding in rats (Balasubramaniam et al. J. Med. Chem. 1994, 37, 811-815). This peptide, however, did not bind to SK-N-MC cells with Y-1 receptors. Since centrally truncated NPY analogs have been shown to bind Y-1 receptors, we synthesized similar analogs of [D-Trp(32)]NPY and investigated their Y-1 (SK-N-MC) and Y-2 (SK-N-BE2) receptor affinities and their properties in human erythroleukemia (HEL) cells. None of the analogs with D-Trp(32) mobilized intracellular calcium, [Ca2]i, in HEL cells. Although Des-AA(6-24)[Aoc(6)]NPY and the corresponding D-Trp(32) analog exhibited no affinity to Y-1 receptors, Des-AA(7-24)[Aoc(6),D-Trp(32)] NPY(6) exhibited weak binding. Replacing Pro(5) in 6 with D-Ala to stabilize the central chain reversal, and hence the antiparallel alignment of the N- and C-terminal regions known to be important for Y-1 binding, resulted in an analog, Des-AA(7-24)[D-Ala(5),Aoc(6),D-Trp(32)]NPY (7), which exhibited moderate antagonist potency in attenuating NPY effects on cAMP and [Ca2+]i, in SK-N-MC and HEL cells, respectively. This analog also shifted the dose-response curve of NPY on blood pressure in anesthetized rats. Deletion of only the 7-17 and/or the incorporation of N-Me-Ala(5), superior beta-turn stabilizer, in 7 did not improve the Y-1 receptor affinity. Des-AA(7-24)[D-Ala(5), Gly(6),D-Trp(32)]NPY exhibited an affinity similar to that of 7, suggesting that a long spacer arm is not necessary for efficient Y-1 receptor interaction. Locking the antiparallel alignment via a 2/26 or 2/27 lactam bridge did not improve the binding. Finally, replacement of D-Ala(5) in 7 with D-Trp dramatically increased both the binding and the antagonistic potencies. Modeling based on the avian pancreatic polypeptide X-ray structure suggested that analogs which have the N- and C-terminal regions in close proximity might exhibit good binding, and that the D-Trp(32) substitution may induce a beta-turn that could be important for exhibiting antagonism. A systematic investigation has resulted in the development of relatively potent Y-1 receptor antagonists. Further structure-activity studies with these compounds and those previously reported by us and other investigators should result in the development of long-acting and receptor selective antagonists.

    Topics: Amino Acid Sequence; Animals; Calcium; Humans; Leukemia, Erythroblastic, Acute; Molecular Sequence Data; Neuropeptide Y; Rats; Rats, Sprague-Dawley; Receptors, Neuropeptide Y; Tumor Cells, Cultured

1996
Structure-activity relationship of novel pentapeptide neuropeptide Y receptor antagonists is consistent with a noncontinuous epitope for ligand-receptor binding.
    Molecular pharmacology, 1995, Volume: 48, Issue:3

    We report the first systematic study on short peptide structure affinity and activity for the neuropeptide Y (NPY) receptor. A series of linear pentapeptides has been synthesized that display affinities in the low micromolar range toward rat brain NPY receptors. Furthermore, some of these compounds competitively antagonize the Y1-type NPY receptor-mediated increase in cytosolic Ca2+ in human erythroleukemic (HEL) cells. The inactive NPY carboxyl-terminal pentapeptide (Thr-Arg-Gln-Arg-Tyr-NH2; IC50 > 100 microM) was modified by replacing threonine with an aromatic amino acid and glutamine with leucine. This resulted in a series of pentapeptides with dramatically improved affinity (IC50 = 0.5-4 microM) for the rat brain receptor. The structure-affinity data suggest that these peptides may represent a noncontinuous epitope containing the amino-terminal tyrosine and the carboxyl-terminal residues Arg-35 and Tyr-36 of NPY.

    Topics: Amino Acid Sequence; Animals; Binding, Competitive; Brain; Calcium; Cell Membrane; Epitopes; Humans; Intracellular Fluid; Leukemia, Erythroblastic, Acute; Ligands; Male; Molecular Sequence Data; Neuropeptide Y; Peptides; Rats; Rats, Sprague-Dawley; Receptors, Neuropeptide Y; Structure-Activity Relationship; Tritium; Tumor Cells, Cultured

1995
High-affinity neuropeptide Y receptor antagonists.
    Proceedings of the National Academy of Sciences of the United States of America, 1995, Sep-26, Volume: 92, Issue:20

    Neuropeptide Y (NPY) is one of the most abundant peptide transmitters in the mammalian brain. In the periphery it is costored and coreleased with norepinephrine from sympathetic nerve terminals. However, the physiological functions of this peptide remain unclear because of the absence of specific high-affinity receptor antagonists. Three potent NPY receptor antagonists were synthesized and tested for their biological activity in in vitro, ex vivo, and in vivo functional assays. We describe here the effects of these antagonists inhibiting specific radiolabeled NPY binding at Y1 and Y2 receptors and antagonizing the effects of NPY in human erythroleukemia cell intracellular calcium mobilization perfusion pressure in the isolated rat kidney, and mean arterial blood pressure in anesthetized rats.

    Topics: Amino Acid Sequence; Animals; Brain; Calcium; Cell Line; Humans; Kidney; Kinetics; Leukemia, Erythroblastic, Acute; Male; Mammals; Molecular Sequence Data; Neuroblastoma; Neuropeptide Y; Organ Specificity; Peptides; Rabbits; Rats; Rats, Sprague-Dawley; Receptors, Neuropeptide Y; Structure-Activity Relationship; Swine; Tumor Cells, Cultured

1995
The role of extracellular calcium in the neuropeptide-Y-induced increase in cytosolic calcium in human erythroleukemic (HEL) cells.
    Molecular and cellular neurosciences, 1994, Volume: 5, Issue:5

    Cytosolic calcium changes were followed in human erythroleukemic (HEL) cells loaded with the fluorescent probe fura-2. Peak increases in cytosolic calcium were reduced by two-thirds in cells suspended in Ca(2+)-free medium, suggesting that calcium entry significantly contributes to the increases in cytosolic calcium after NPY receptor stimulation. To establish if Ca2+ entry was a direct consequence of receptor stimulation or indirectly via depletion of Ca2+ stores, the latter were totally or partially depleted by treatment with cyclopiazonic acid or alpha-thrombin, respectively, in Ca(2+)-free medium. Partial depletion markedly diminished and full depletion suppressed the NPY-induced response in Ca(2+)-free medium. After full depletion, the recovery of the NPY-induced increase in cytosolic calcium was dependent on the length of [Ca2+]e reexposure, suggesting a direct entry of Ca2+ to the storage sites followed by release to the cytosol. After partial depletion, transient reexposure to [Ca2+]e did not by itself increase cytosolic calcium levels or refill the stores as NPY stimulation did not increase cytosolic calcium if [Ca2+]e was chelated prior to stimulation. However, if partially depleted cells were exposed to NPY in the presence of readded [Ca2+]3, the peak calcium response was similar to that of control cells, indicating that partially depleted calcium stores can be refilled from extracellular sources only if NPY receptors are stimulated. Analysis of the data suggests that in HEL cells the entry of calcium and mobilization from intracellular stores are in series processes and that entry is triggered by intracellular levels only under extreme depletion, while under physiological conditions calcium entry is coupled to receptor stimulation.

    Topics: Calcium; Calcium Channel Blockers; Calcium-Transporting ATPases; Cells, Cultured; Cytosol; Dose-Response Relationship, Drug; Ethanol; Extracellular Space; Humans; Indoles; Leukemia, Erythroblastic, Acute; Neuropeptide Y; Osmolar Concentration; Thrombin

1994
Characterization of the neuropeptide Y-induced intracellular calcium release in human erythroleukemic cells.
    Molecular pharmacology, 1992, Volume: 41, Issue:4

    Human erythroleukemic (HEL) cells, loaded with fura-2, respond to neuropeptide Y (NPY) with a fast and transient increase in intracellular calcium. The Y1 receptor-specific agonist (Leu-31,Pro-34)-NPY is 4-fold more potent and the carboxyl-terminal fragment NPY13-36 is 150-fold less potent than NPY. Thus, it is concluded that the response is mediated through the activation of a Y1 type of NPY receptor. HEL cells do not respond to a second addition of NPY but do respond to a further addition of alpha-thrombin (alpha-T). However, in a calcium-free medium, prior stimulation with NPY largely inhibits a subsequent response to alpha-T. Moreover, prior stimulation with alpha-T in the absence of external calcium completely prevents the response to the addition of NPY, indicating a common effector pathway. The latter is further reinforced by using thapsigargin (TG), which has been shown to deplete the Inositol 1,4,5-trisphosphate-dependent calcium pool in other systems. HEL cells preincubated with TG in calcium-free medium fail to respond to either NPY or alpha-T. Likewise, prior stimulation with NPY or alpha-T in calcium-free medium significantly inhibits the response to TG. Preincubation of cells with phorbol esters strongly inhibits the NPY-induced release of intracellular Ca2+ in HEL cells, an effect that is partially prevented by preincubation of the cells with H7, a protein kinase C inhibitor. However, neither the homologous nor the apparent heterologous desensitization of the NPY receptor can be prevented by H7. It is concluded that NPY releases intracellular Ca2+ from an inositol 1,4,5-trisphosphate-sensitive calcium pool, which is restored by external calcium, and that NPY receptor desensitization is protein kinase C independent.

    Topics: 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; Calcium; Enzyme Activation; Erythrocytes; Fura-2; Humans; Inositol 1,4,5-Trisphosphate; Isoquinolines; Leukemia, Erythroblastic, Acute; Neuropeptide Y; Piperazines; Protein Kinase C; Spectrometry, Fluorescence; Terpenes; Thapsigargin; Tumor Cells, Cultured

1992
Distinction of NPY receptors in vitro and in vivo. I. NPY-(18-36) discriminates NPY receptor subtypes in vitro.
    The American journal of physiology, 1990, Volume: 259, Issue:1 Pt 1

    We studied the possibility of multiple neuropeptide Y (NPY) receptor subtypes. NPY-stimulated Ca2+ mobilization in human erythroleukemia (HEL) cells was used to screen a number of NPY analogues. The potencies of three of these analogues [peptide YY (PYY), [D-Tyr-36]NPY, and NPY-(18-36)] were compared with that of NPY in the following model systems: Ca2+ mobilization and inhibition of adenosine 3',5'-cyclic monophosphate accumulation in HEL cells, potentiation of vasoconstriction in the isolated rabbit ear artery, reduction of cutaneous microvascular perfusion in the rat digit, and inhibition of [3H]serotonin release in rat brain. In each of the five models, PYY was a full agonist that exhibited a similar or slightly higher potency than NPY, whereas [D-Tyr-36]NPY and NPY-(18-36) were partial agonists with lower potencies: NPY-(18-36) had a lower potency and efficacy than [D-Tyr-36]NPY in HEL cells and the rabbit ear artery, but was more effective than [D-Tyr-36]NPY for constricting cutaneous microvasculature and inhibiting serotonin release. Because of its weak partial agonism, we also tested NPY-(18-36) as an antagonist of NPY-stimulated Ca2+ mobilization in HEL cells. NPY-(18-36) shifted the NPY concentration-response curve to the right with a KB affinity value of 297 nM. In summary, [D-Tyr-36]NPY and NPY-(18-36) are partial agonists, the relative potency of which varies between systems. These data demonstrate the presence of multiple NPY receptor subtypes. We propose a modified classification scheme of NPY receptor subtypes.

    Topics: Animals; Calcium; Cell Line; Cerebral Cortex; Cyclic AMP; Humans; Kinetics; Leukemia, Erythroblastic, Acute; Neuropeptide Y; Norepinephrine; Peptide Fragments; Rats; Receptors, Neuropeptide Y; Receptors, Neurotransmitter; Regional Blood Flow; Serotonin; Skin; Structure-Activity Relationship; Tumor Cells, Cultured; Vasoconstrictor Agents

1990
Neuropeptide Y mobilizes intracellular Ca2+ and increases inositol phosphate production in human erythroleukemia cells.
    Biochemical and biophysical research communications, 1989, Dec-29, Volume: 165, Issue:3

    The intracellular concentration of free Ca2+ was monitored by measuring the fluorescence of fura-2 loaded Human Erythroleukemia Cells. Neuropeptide Y (NPY) increased intracellular Ca2+ in a dose-dependent manner and the 50% effective concentration was 2 nM. Chelation of extracellular Ca2+ by EGTA did not reduce the NPY-mediated increase in cytoplasmic Ca2+, indicating that the increase in fluorescence was due to the release of intracellular Ca2+. A second dose of NPY, after intracellular Ca2+ had returned to basal levels, failed to elicit a response, indicating that the NPY receptor had undergone desensitization. In similar experiments, NPY increased the formation of inositol phosphates, suggesting that the mobilization of Ca2+ from intracellular stores in HEL cells was secondary to the generation of inositol phosphates and stimulation of phospholipase C.

    Topics: Benzofurans; Calcium; Dose-Response Relationship, Drug; Egtazic Acid; Fluorescent Dyes; Fura-2; Humans; Inositol Phosphates; Kinetics; Leukemia, Erythroblastic, Acute; Neuropeptide Y; Spectrometry, Fluorescence; Tumor Cells, Cultured; Type C Phospholipases

1989
Interaction between alpha 2-adrenergic and NPY receptor pathways in human erythroleukemia cells.
    Clinical and experimental hypertension. Part A, Theory and practice, 1989, Volume: 11 Suppl 1

    Neuropeptide Y (NPY) appears to be a transmitter of the sympathetic nervous system, and its actions are similar to those of alpha 2-adrenergic receptor stimulation. In human erythroleukemia (HEL) cells, both NPY and epinephrine (acting through alpha 2-adrenergic receptors) inhibit adenylate cyclase and mobilize intracellular Ca++. We investigated possible interactions between NPY and epinephrine. In radioligand binding assays NPY did not alter antagonist or agonist binding to alpha 2-adrenergic receptors. NPY and epinephrine did not act synergistically to elevate intracellular Ca++. Neither agent alone, nor both together, affected the intracellular pH of HEL cells. Preincubation with NPY (like epinephrine) redistributed the alpha 2-adrenergic receptors away from the cell surface and into a sequestered pool.

    Topics: Calcium; Drug Synergism; Epinephrine; Humans; Hydrogen-Ion Concentration; Leukemia, Erythroblastic, Acute; Neuropeptide Y; Receptors, Adrenergic, alpha; Receptors, Neuropeptide Y; Receptors, Neurotransmitter; Tumor Cells, Cultured

1989
Neuropeptide Y mobilizes Ca2+ and inhibits adenylate cyclase in human erythroleukemia cells.
    The American journal of physiology, 1988, Volume: 255, Issue:6 Pt 1

    Neuropeptide Y (NPY), a peptide often coreleased with catecholamines, appears to be an important component of the sympathetic nervous system, but little is known about the molecular basis of its action. We introduce here human erythroleukemia (HEL) cells as a new model system for studies of NPY action. NPY inhibited adenosine 3,5'-cyclic monophosphate (cAMP) accumulation in HEL cells with a 50% effective concentration (EC50) of 3 nM. Additionally NPY increased intracellular Ca2+, as assessed by fura-2 fluorescence, with a similar EC50. Pretreatment with pertussis toxin blocked both responses, suggesting the involvement of one or more G proteins. Chelating extracellular Ca2+ with EGTA did not reduce the Ca2+ signal, demonstrating mobilization from intracellular stores rather than influx. Experiments with various agents demonstrated that the Ca2+ mobilization was not secondary to lowering of cAMP levels, formation of arachidonic acid products, or Na+-H+ exchange. Ca2+ mobilization also did not appear to be associated with inositol phosphate generation. In conclusion, we demonstrate for the first time that NPY, in addition to inhibiting adenylate cyclase, also can elevate intracellular Ca2+. HEL cells should prove useful in further studies of the molecular basis of NPY action.

    Topics: Adenylyl Cyclase Inhibitors; Benzofurans; Calcium; Cell Line; Fluorescent Dyes; Fura-2; Humans; Kinetics; Leukemia, Erythroblastic, Acute; Neuropeptide Y; Phosphatidylinositols

1988