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Pharmacological characterization of ¹²⁵I-1229U91 binding to Y1 and Y4 neuropeptide Y/peptide YY receptors

JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS 2000年第1期293卷 275-280页

作者： Schober, DA Gackenheimer, SL Heiman, ML Gehlert, DR Eli Lilly & Co Lilly Corp Ctr Lilly Res Labs Lilly Neurosci Indianapolis IN 46285 USA Eli Lilly & Co Lilly Corp Ctr Lilly Res Labs Lilly Endocrine Res Indianapolis IN 46285 USA

1229U91 (GW1229 or GR231118) [IIe,Glu,Pro,Dpr,Tyr, Arg,Leu,Arg,Tyr-NH2)2 cyclic (2,4'),(2'4)-diamide] has been reported by several research groups to be a potent antagonist at the Y1 neuropeptide Y (NPY) receptor subtype. However, 1229U91 also displaces I-125-peptide YY (PYY) with high affinity from the Y4 subtype. Previously, we reported that 1229U91 had full agonist properties for the Y4 receptor. To characterize the pharmacological properties of 1229U91 directly, we had it radioiodinated with the chloromine-T method. I-125-1229U91 bound to cell lines expressing the human Y1 and Y4 receptors with high affinity. The K-d and B-max for I-125-1229U91 binding to Y1 were 14.9 pM and 1458 fmol/mg protein, respectively. The Y4 receptor bound I-125-1229U91 with a K-d of 12.5 pM and a B-max of 1442 fmol/mg protein. When competing I-125-1229U91 binding from Y1 and Y4 receptors, a similar rank order of potency was observed: 1229U91 > [Leu(31),pro(34)]-NPY greater than or equal to [Leu(31),pro(34)]-PYY > PYY greater than or equal to NPY > NPY(2-36) > PYY(3-36). Pancreatic polypeptide (PP) potently displaced I-125-1229U91 from the Y4 receptor, but displayed little affinity for Y1. In autoradiographic studies with rat brain sections, I-125-1229U91 bound with a distribution similar to that reported for the Y1 receptor when localized with I-125-[Leu(31),Pro(34)]-PYY. Brain regions exhibiting binding sites for I-125-PP were not detected with this radioligand. Those include the interpeduncular nucleus and the periventricular nucleus of the hypothalamus. Furthermore, I-125-labeled rat PP was not displaced from these areas with 10 nM 1229U91. Thus, I-125-1229U91 is a high affinity Y1 and Y4 radioligand and binds with a distribution in the rat brain consistent with the localization of the Y1 receptor.

关键词：放射自显影术结合竞争性/药物作用脑化学/药物作用 CHO细胞克隆分子仓鼠亚科碘放射性同位素/诊断应用动力学膜/药物作用膜/代谢神经肽Y/拮抗剂和抑制剂神经肽Y/代谢神经肽类/拮抗剂和抑制剂胰多肽/代谢肽类环/药代动力学大鼠 Sprague-Dawley 受体神经肽Y/拮抗剂和抑制剂受体神经肽Y/代谢动物人类男(雄)性大鼠

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Distribution and characterization of natriuretic peptide receptors in the kidney of the toad, Bufo marinus

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GENERAL AND COMPARATIVE ENDOCRINOLOGY 1999年第2期115卷 244-253页

作者： Meier, SK Toop, T Donald, JA Deakin Univ Sch Biol & Chem Sci Geelong Vic 3217 Australia

The location and characteristics of atrial natriuretic peptide binding sites in the kidney of the toad, Bufo marinus, were determined. Specific (125)I-rANP binding sites were observed on glomeruli and blood vessels, but little if any binding was observed over regions corresponding to the renal tubules. (125)I-rANP binding in tissue sections and/or isolated membranes was completely displaced in the presence of 1 mu M rat ANP, frog ANP, and porcine C-type natriuretic peptide (membranes only);however, residual binding remained after incubation with 1 mu M Of the NPR-C ligand, C-ANF, indicating the presence of two distinct binding sites. Electrophoresis of kidney membranes cross-linked to (125)I-rANP identified specific bands at approximately 70 and 140 kDa which correspond to the monomeric mass of NPR-C and the guanylate cyclase receptors, respectively. In addition, rat ANP, frog ANP, and porcine CNP stimulated a significant increase in cGMP production rates in membrane preparations, while C-ANF had no stimulatory effect. Two partial cDNA clones generated using primers based on conserved regions of vertebrate natriuretic peptide receptors showed high homology to an NPR-C and the natriuretic peptide guanylate cyclase receptors (NPR-GC), respectively. This study provides evidence that the kidney of B. marinus contains both NPR-C and NPR-GC and that the glomerulus is potentially the principal site of ANP regulation in the kidneys. (C) 1999 Academic Press.

关键词：氨基酸序列放射自显影术碱基序列结合竞争性/药物作用海蟾蜍/生理学克隆分子交联试剂电泳聚丙烯酰氨凝胶鸟苷酸环化酶/代谢肾/解剖学和组织学肾/酶学肾/代谢配体膜/化学膜/代谢分子序列数据分子量 RNA 信使/生物合成 RNA 信使/遗传学受体心钠素/代谢动物

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Multiple nonfunctional alleles of CCR5 are frequent in various human populations

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BLOOD 2000年第5期96卷 1638-1645页

作者： Blanpain, C Lee, B Tackoen, M Puffer, B Boom, A Libert, F Sharron, M Wittamer, V Vassart, G Doms, RW Parmentier, M Free Univ Brussels IRIBHN Lab Histol Neuroanat & Neuropathol B-1070 Brussels Belgium Free Univ Brussels Serv Genet Med B-1070 Brussels Belgium Univ Penn Dept Pathol & Lab Med Philadelphia PA 19104 USA

CCR5 is the major coreceptor for macrophage-tropic strains of the human immunodeficiency virus type I(HIV-1), Homozygotes for a 32-base pair (bp) deletion in the coding sequence of the receptor (CCR5 Delta 32) were found to be highly resistant to viral infection, and CCR5 became, therefore, one of the paradigms illustrating the influence of genetic variability onto individual susceptibility to infectious and other diseases. We investigated the functional consequences of 16 other natural CCR5 mutations described in various human populations. We found that 10 of these variants are efficiently expressed at the cell surface, bind [I-125]-MIP-1 beta with affinities similar to wtCCR5, respond functionally to chemokines, and act as HIV-1 coreceptors. In addition to Delta 32, six mutations were characterized by major alterations in their functional response to chemokines, as a consequence of intracellular trapping and poor expression at the cell surface (C101X, FS299), general or specific alteration of ligand binding affinities (C20S, C178R, A29S), or relative inability to mediate receptor activation (L55Q), A29S displayed an unusual pharmacological profile, binding and responding to MCP-2 similarly to wtCCR5, but exhibiting severely impaired binding and functional responses to MIP-1 alpha, MIP-1 beta, and RANTES, In addition to Delta 32, only C101X was totally unable to mediate entry of HIV-1. The fact that nonfunctional CCR5 alleles are relatively frequent in various human populations reinforces the hypothesis of a selective pressure favoring these alleles, (C) 2000 by The American Society of Hematology.

关键词：等位基因氨基酸序列结合竞争性/药物作用 CHO细胞细胞系仓鼠亚科细胞因子类/药理学剂量效应关系药物基因表达 HIV包膜蛋白质gp120/遗传学 HIV包膜蛋白质gp120/代谢 HIV-1/遗传学碘放射性同位素/诊断应用萤光素酶类/遗传学萤光素酶类/代谢分子序列数据突变蛋白质结合放射配体测定受体 CCR5/遗传学受体 CCR5/代谢受体细胞表面/遗传学受体细胞表面/代谢重组融合蛋白质类/遗传学重组融合蛋白质类/代谢动物人类

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A simple, solid-phase binding assay for the nuclear import receptor karyopherin α.: Part 1:: Direct binding

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BIOORGANIC & MEDICINAL CHEMISTRY LETTERS 2000年第9期10卷 951-954页

作者： Connolly, MD Park, SB Reedy, BM Standaert, RF Texas A&M Univ Dept Chem College Stn TX 77842 USA

The nuclear import receptor karyopherin alpha recognizes nuclear localization signals (NLSs), peptides that direct the transport of proteins into the nucleus. A simple, colorimetric assay has been developed to facilitate the identification and comparison of karyopherin ligands by direct and competitive binding using NLSs immobilized on the solid phase (TentaGel(R) resin). (C) 2000 Elsevier Science Ltd, All rights reserved.

关键词：碱性磷酸酶/拮抗剂和抑制剂氨基酸序列抗原多瘤病毒转化/化学结合竞争性/药物作用生物素/化学细胞核/药物作用细胞核/代谢比色法指示剂和试剂吲哚类/化学分子序列数据核蛋白质类/药物作用核蛋白质类/代谢肽类/化学合成肽类/药理学蛋白质结合受体胞质和核/药物作用受体胞质和核/代谢抗生蛋白链菌素 α核胞浆转运蛋白类

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Selectivity of recombinant human leukotriene D₄, leukotriene B₄, and lipoxin A₄ receptors with aspirin-triggered 15-epi-LXA₄ and regulation of vascular and inflammatory responses

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AMERICAN JOURNAL OF PATHOLOGY 2001年第1期158卷 3-9页

作者： Gronert, K Martinsson-Niskanen, T Ravasi, S Chiang, N Serhan, CN Brigham & Womens Hosp Ctr Expt Therapeut & Reperfus Injury Dept Anesthesia Perioperat & Pain Med Boston MA 02115 USA Harvard Univ Sch Med Boston MA USA

Aspirin-triggered Lipoxin A(4) (ATL, 15-epi-LXA(4)) and leukotriene D-4 (LTD4) possess opposing vascular actions mediated via receptors distinct from the LXA(4) receptor (ALX) that is involved in leukocyte trafficking. Here, we identified these receptors by nucleotide sequencing and demonstrate that LTD4 receptor (CysLT(1)) is induced in human vascular endothelia by interkukin-1 beta. Recombinant CysLT(1) receptor gave stereospecific binding with both [H-3]-LTD4 and a novel labeled mimetic of ATL ([H-3]-ATLa) that was displaced with LTD4 and ATLa (similar to IC50 0.2 to 0.9 nmol/ L), but not with a bioinactive ATL isomer. The clinically used CysLT(1) receptor antagonist, Singulair, showed a lower rank order for competition with [H-3]-ATLa (IC50 approximate to 8.3 nmol/L). In contrast, LTD4 was an ineffective competitive ligand for recombinant ALX receptor with [H-3]-ATLa, and ATLa did not compete for [H-3]-LTB4 binding with recombinant LTB4 receptor. Endogenous murine CysLT(1) receptors also gave specific [H-3]-ATLa binding that was displaced with essentially equal affinity by LTD, or ATLa, Systemic ATLa proved to be a potent inhibitor (>50%) of CysLT(1)-mediated vascular leakage in murine skin (200 mug/kg) in addition to its ability to block polymorphonuclear leukocyte recruitment to dorsal air pouch (4 mug/kg). These results indicate that ATL and LTD, bind and compete with equal affinity at CysLT(1), providing a molecular basis for aspirin-triggered LXs serving as a local damper of both vascular CysLT(1) signals as well as ALX receptor-regulated polymorphonuclear leukocyte traffic.

关键词：阿司匹林/药理学结合竞争性/药物作用 COS细胞毛细血管通透性/药物作用细胞系剂量效应关系药物基因表达羟基花生四烯酸类/化学羟基花生四烯酸类/代谢羟基花生四烯酸类/药理学炎症/病理学炎症/预防和控制白三烯D4/化学白三烯D4/代谢白三烯D4/药理学脂氧素类膜蛋白质类小鼠近交BALBC 中性白细胞/药物作用中性白细胞/病理学 RNA/遗传学 RNA/代谢受体细胞表面/遗传学受体细胞表面/代谢受体甲酰肽受体白三烯/遗传学受体白三烯/代谢受体白三烯B4/遗传学受体白三烯B4/代谢受体脂氧素重组蛋白质类/代谢立体异构现象氚/诊断应用动物人类男(雄)性小鼠

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Conantokin G is an NR2B-selective competitive antagonist of N-methyl-D-aspartate receptors

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MOLECULAR PHARMACOLOGY 2000年第3期58卷 614-623页

作者： Donevan, SD McCabe, RT Univ Utah Dept Neurol Salt Lake City UT USA Cognetix Inc Salt Lake City UT USA

Conantokin G (Con G) is a 17-amino-acid peptide antagonist of N-methyl-D-aspartate (NMDA) receptors isolated from the venom of the marine cone snail, Conus geographus. The mechanism of action of Con G has not been well defined;both competitive and noncompetitive interactions with the NMDA-binding site have been proposed. In this study the mechanism of action and subunit selectivity of Con G was examined in whole-cell voltage-clamp recordings from cultured neurons and in two electrode voltage-clamp recordings from Xenopus oocytes expressing recombinant NMDA receptors. Con G was a potent and selective antagonist of NMDA-evoked currents in murine cortical neurons (IC50 = 480 nM). The slow onset of Con G block could be prevented by coapplication with high concentrations of NMDA or of the competitive antagonist (RS)-3-(2-carboxypiperazine-4-yl)-propyl-1-phosphonic acid. Furthermore, in oocytes expressing NR1a/NR2B receptors, Con G produced a rightward shift in the concentration-response curve for NMDA, providing support for a competitive interaction with the NMDA-binding site. Con G produced an apparent noncompetitive shift in the concentration-response curve for spermine potentiation of NMDA responses, but this was due to spermine-induced enhancement of Con G block. Spermine produced a similar enhancement of DL-2-amino-S-phosphopentanoic acid block. Finally, Con G selectively blocked NMDA receptors containing the NR2B subunit. These results demonstrate that Con G is a subunit-specific competitive antagonist of NMDA receptors. The unique subunit selectivity profile of Con G may explain its favorable in vivo profile compared with nonselective NMDA antagonists.

关键词：结合竞争性/药物作用细胞培养的芋螺毒素类/药理学药物相互作用电生理学兴奋性氨基酸拮抗剂/药理学神经元/药物作用神经元/代谢聚胺类/药理学受体 N-甲基-D-天冬氨酸/拮抗剂和抑制剂转染光滑爪蟾动物小鼠

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Regulation of the type III InsP₃ receptor by InsP₃ and ATP

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BIOPHYSICAL JOURNAL 2000年第1期79卷 271-278页

作者： Hagar, RE Ehrlich, BE Yale Univ Dept Pharmacol New Haven CT 06520 USA Yale Univ Dept Cellular & Mol Physiol New Haven CT 06520 USA Univ Connecticut Ctr Hlth Dept Physiol Farmington CT 06030 USA

Many hormones and neurotransmitters raise intracellular calcium (Ca2+) by generating InsP(3) and activating the inositol 1,4,5-trisphosphate receptor (InsP(3)R). Multiple isoforms with distinct InsP(3) binding properties (Cardy et al., 1997) have been identified (Morgan et at., 1996). The type III InsP(3)R lacks Ca2+-dependent inhibition, a property that makes it ideal for signal initiation (Hagar et al., 1998). Regulation of the type III InsP(3)R by InsP(3) and ATP was explored in detail using planar lipid bilayers. In comparison to the type I InsP(3)R, the type III InsP(3)R required a higher concentration of InsP(3) to reach maximal channel activity (EC50 of 3.2 mu M versus 0.5 mu M for the types III and I InsP(3)R, respectively). However, the type III InsP(3)R did reach a 2.5-fold higher level of activity. Although activation by InsP(3) was isoform-specific, regulation by ATP was similar for both isoforms. In the presence of 2 mu M InsP(3), low ATP concentrations (<6 mM) increased the open probability and mean open time. High ATP concentrations (>6 mM) decreased channel activity. These results illustrate the complex nature of type III InsP(3)R regulation. Enhanced channel activity in the presence of high InsP(3) may be important during periods of prolonged stimulation, whereas allosteric modulation by ATP may help to modulate intracellular Ca2+ signaling.

关键词：腺苷三磷酸/代谢腺苷三磷酸/药理学别构调节/药物作用结合竞争性/药物作用钙通道/药物作用钙通道/代谢剂量效应关系药物内质网/药物作用内质网/代谢肌醇1 4 5-三磷酸/代谢肌醇1 4 5-三磷酸/药理学肌醇1 4 5-三磷酸受体胰岛素瘤/代谢胰岛素瘤/病理学微粒体/药物作用微粒体/代谢蛋白质亚型/药物作用蛋白质亚型/代谢受体胞质和核/药物作用受体胞质和核/代谢底物特异性肿瘤细胞培养的动物大鼠

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Heparin and heparan sulfate bind interleukin-10 and modulate its activity

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BLOOD 2000年第5期96卷 1879-1888页

作者： Salek-Ardakani, S Arrand, JR Shaw, D Mackett, M Christie Hosp NHS Trust CRC Mol Biol Sect Paterson Inst Canc ResMol Biol Grp Manchester M20 4BX Lancs England

Glycosaminoglycans (GAG) are a group of negatively charged molecules that have been shown to bind and directly regulate the bioactivity of growth factors and cytokines such as basic fibroblast growth factor, transforming growth factor-beta, IL-7, and interferon-gamma. The ability of GAG to interact with human IL-10 (hIL-10) and the effect of these interactions on its biologic activity were analyzed. It was demonstrated by affinity chromatography that hIL-10 binds strongly to heparin-agarose at physiological pH, Biosensor-based binding kinetic analysis indicated an equilibrium dissociation constant, K-d, Of 54 nmol/L for this interaction. Human IL-10 stimulated CD16 and CD64 expression on the monocyte/macrophage population within peripheral blood mononuclear cells, with optimal concentrations between 1 and 10 ng/mL. Soluble heparin, heparan sulfate, chondroitin sulfate, and dermatan sulfate were shown to inhibit the hIL-10-induced expression of CD16 and CD64 in a concentration-dependent manner. Heparin and heparan sulfate were most effective with IC50 values of 100 to 500 mu g/mL Considerably higher concentrations of dermatan sulfate and chondroitin 4-sulfate were required with an IC50 Of 2000 to 5000 mu g/mL, whereas chondroitin 6-sulfate was essentially inactive. The antagonistic effect of heparin on hIL-10 activity was shown to be dependent on N-sulfation, inasmuch as de-N-sulfated heparin had little or no inhibitory effect on the IL-10- induced expression of CD16, whereas the effect of de-O-sulfated heparin was comparable to that of unmodified heparin. Furthermore, the inhibition of cell-bound proteoglycan sulfation reduced the hIL-10-mediated expression of CD16 molecules on monocytes/macrophages. Taken together, these findings support the hypothesis that soluble and cell-surface GAG and, in particular, their sulfate groups are important in binding and modulation of hIL-10 activity. (C) 2000 by The American Society of Hematology.

关键词：氨基酸序列抗原 CD/药物作用抗原 CD/代谢结合竞争性/药物作用细胞培养的氯酸盐类/药理学色谱法亲和剂量效应关系药物流式细胞术葡糖氨基聚糖类/药理学肝素/代谢肝素/药理学类肝素硫酸盐/代谢类肝素硫酸盐/药理学白细胞介素10/代谢白细胞介素10/药理学动力学白细胞单核/细胞学白细胞单核/药物作用白细胞单核/代谢巨噬细胞/细胞学巨噬细胞/药物作用巨噬细胞/代谢分子序列数据单核细胞/细胞学单核细胞/药物作用单核细胞/代谢受体 IgG/药物作用受体 IgG/代谢重组蛋白质类/代谢重组蛋白质类/药理学琼脂糖/类似物和衍生物人类

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The bacterial elicitor flagellin activates its receptor in tomato cells according to the address-message concept

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PLANT CELL 2000年第9期12卷 1783-1794页

作者： Meindl, T Boller, T Felix, G Friedrich Miescher Inst CH-4002 Basel Switzerland

flg22, a peptide corresponding to the most conserved domain of bacterial flagellin, acts as a potent elicitor in plants. Here, we have used an iodinated derivative of flg22 (I-125-labeled Tyr-flg22) as a molecular probe for the flagellin receptor in tomato cells. This radioligand showed rapid binding to a single class of specific, saturable, high-affinity receptor sites in intact cells and membrane preparations. Binding, although essentially nonreversible under physiological conditions, was not covalent, and chemical cross-linking was required to specifically label a single polypeptide of 115 kD. Intact flagellin and elicitor-active flagellin peptides but not biologically inactive analogs efficiently competed for binding of radioligand. Peptides lacking the C terminus of the conserved domain, previously found to act as competitive antagonists of elicitor action in tomato cells, also competed for binding of radioligand. Thus, this novel, high-affinity binding site exhibited all the characteristics expected of a functional receptor of bacterial flagellin. For a model of receptor activation, we propose a two-step mechanism according to the address-message concept, in which binding of the N terminus (address) is the first step and activation of responses with the C terminus (message) is the second step.

关键词：碱类氨基酸序列结合竞争性/药物作用剂量效应关系药物鞭毛蛋白/化学鞭毛蛋白/代谢氢离子浓度碘放射性同位素/诊断应用番茄/细胞学番茄/代谢膜/代谢微粒体/代谢分子序列数据寡肽类/化学寡肽类/代谢寡肽类/药理学受体细胞表面/代谢序列同源性氨基酸

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Quantal currents at single-site central synapses

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JOURNAL OF PHYSIOLOGY-LONDON 2000年第1期526卷 3-11页

作者： Auger, C Marty, A UCL Dept Physiol London WC1 E6BT England Max Planck Inst Biophys Chem Arbeitsgrp Zellulare Neurobiol D-37077 Gottingen Germany

The mode of operation of synaptic transmission has been primarily worked out at the vertebrate neuromuscular junction, thus providing a framework for the interpretation of studies at central synapses. However, differences have been found between the two systems, and a coherent model is still lacking for central synapses. Research in this area revolves around several questions. (1) Is the variability of quantal amplitudes determined pre- or postsynaptically? (2) What is the occupancy of postsynaptic receptors following the release of a synaptic vesicle? And (3) does multivesicular release occur at single release sites following one presynaptic action potential? To answer these questions, it is essential to investigate synaptic processes at the level of single release sites. This is technically difficult because of the complex morphology and small dimensions of central synapses. Nevertheless significant advances have been made in the past few years.

关键词：动作电位/药物作用苯二氮|艹卓|类/药理学结合竞争性/药物作用细胞培养的中枢神经系统/细胞学中枢神经系统/药物作用中枢神经系统/代谢诱发电位/药物作用兴奋性突触后电位/药物作用谷氨酸/代谢海马/细胞学海马/药物作用海马/代谢神经元/细胞学神经元/药物作用神经元/代谢膜片钳术受体 AMPA/代谢受体 N-甲基-D-天冬氨酸/代谢受体神经递质/拮抗剂和抑制剂受体神经递质/代谢蜘蛛毒液类/药理学突触/药物作用突触/代谢脊椎动物动物

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