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从蚯蚓中分离出一种能增强离体豚鼠心耳收缩作用的物质。用分子筛层析,阴离子交换层析及高效液相色谱法进行了纯化,进一步分析表明,它是分子量约为30,000daltons的多肽(称为蚯这多肽制剂),可被肾上腺素能受体阻断剂——心得安对抗,能竞争性抑制~3H标记心得舒与大鼠心肌膜制剂内β-肾上腺素能受体的结合,为一种新的β-肾上腺素能受体激动剂。 相似文献
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本文以测定 cAMP 含量为手段,研究了~(60)Co-γ下线800 R 照射及合并β-肾上腺素能刺激剂对小鼠骨髓细胞膜上β-肾上腺素能受体的反应。β-肾上腺素能刺激剂可通过对β-肾上腺能受体作用而引起骨髓细胞内 cAMP 含量改变;照射和异丙基肾上腺素(IPR)均可使 cAMP含量增加,照射以后再注入 IRP 则 cAMP 含量增加的幅度超过单纯照射和 IPR,然而,IPR注入后再照射,cAMP 含量不增加。心得安(PPL)可有效地阻断由照射或 IPR 引起 cAMP升高的反应。 相似文献
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目的:克隆β2-肾上腺素能受体(β2-AR)全长基因片段.方法:根据GenBank中收录的猪β2-AR cDNA序列设计一对引物,以猪肝脏组织总RNA为模板,利用RT-PCR技术扩增目的基因,将其与pUC18载体体外连接,转化感受态大肠杆菌E.coil DH5α,筛选阳性克隆.结果:扩增出一条1257 bp的目的基因片段,该片段编码418个氨基酸.与CenBank中收录的猪β2-AR序列比对,其同源性为99.52%,编码的氨基酸有99.04%相同.结论:成功获得了β2-AR全长基因片段,为该基因的表达和受体筛药模型的建立奠定基础. 相似文献
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2012年度诺贝尔化学奖授予了美国科学家罗伯特.莱夫科维茨(Robert J.Lefkowitz)和布莱恩.克比尔卡(Brian K.Kobilka),以表彰他们在G蛋白偶联受体研究中的贡献。从Robert J.Lefkowitz最初研究β-肾上腺素受体(β-adrenergic receptor,β-AR)减敏机制时发现β-arrestin1至今已有20多年,随着对β-arrestin在细胞信号转导中作用研究的逐渐深入,发现β-arrestin参与β-AR的减敏、内化和降解;近年来又发现,依赖β-arrestin的β-AR信号转导通路具有"偏向激活"现象,并提示这种依赖β-arrestin的"偏向激活"信号转导通路具有心脏保护作用。β-肾上腺素受体阻滞剂的发现和临床应用被视为20世纪药物治疗学上里程碑式的进展,是药物防治心脏疾病的最伟大突破,很多心血管药物都以β-AR为靶点。但是,由于目前受体药物均是针对受体本身的调控,这样在阻断了受体介导的病理性信号通路和功能的同时,也阻断了受体介导的正常生理性信号通路和功能,造成了严重的毒副作用。所以,研发能选择性阻滞β-AR过度激活介导的病理性信号通路和功能的同时,保留受体介导的正常生理性信号通路和功能(如β-arrestin信号通路)的药物,对治疗心血管疾病有重要意义,受体功能选择性的配体药物将成为未来药物的研究方向。该文将回顾β-arrestin的发现过程,综述其与β-AR的相互作用,期望能为心脏疾病的药物治疗提供参考。 相似文献
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β-肾上腺素受体激动对新生大鼠心肌细胞代谢的影响 总被引:2,自引:0,他引:2
为了观察β-肾上腺素受体(β-AR)持续激动对心肌细胞代谢的影响,本工作以培养的新生大鼠心肌细胞为研究对象,采用[^3H]-亮氨酸([^3H]-leucine)掺入法和BCA蛋白分析法检测心肌细胞的蛋白合成代谢与蛋白含量,[^3H]-2-脱氧-D-葡萄糖摄取测定方法检测心肌细胞对葡萄糖的摄取量,并采用蛋白免疫印迹杂交方法检测腺苷酸活化蛋白激酶(adenosine monophosphate activated protein kinase,AMPK)磷酸化程度。结果显示,β-AR激动剂异丙肾上腺素(isoproterenol,ISO)持续刺激心肌细胞48h,心肌细胞[^3H]-leucine掺入量和蛋白质含量与对照组相比均无显著差异。用ISO或去甲肾上腺素(α1-AR特异性拮抗剂哌唑嗪存在下)持续激动β-AR 48h,心肌细胞的葡萄糖摄取量和AMPK磷酸化均显著高于对照组。上述结果表明,β-AR持续激动对培养的新生大鼠心肌细胞蛋白质合成及蛋白质含量没有明显的作用,但可引起葡萄糖摄取量明显增加和AMPK的激活,提示β-AR可能与心肌肥厚过程中能量代谢状态的变化有关。 相似文献
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卢新政 《国外医学:分子生物学分册》1997,19(2):54-57
β肾上腺素能受体属于G蛋白偶联受体,分为β1,β2、β3受体亚型,这些亚型具有相似的高级结构。各个亚型的基因克基因克隆表明它们由不同的基因编码。不同亚型的基因具有明显的同源性。 相似文献
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β-肾上腺素能受体在NO抑制小鼠回肠自主收缩中的作用 总被引:2,自引:0,他引:2
目的:观察一氧化氮(nitric oxide,NO)供体左旋精氨酸(L-argnine,L—Arg)对小鼠回肠自主收缩幅度的影响,探讨肛肾上腺素能受体在NO抑制小鼠回肠自主收缩中的作用。方法:应用张力换能器记录标本自主收缩的方法,以回肠肌条自主收缩幅度变化为指标,观察一氧化氮合酶(nitric oxide synthase,NOS)抑制剂L-NNA,可溶性鸟苷酸环化酶(soluble guanylyl cyclase,sGC)抑制剂ODQ(1H-[1,2,4]oxadiazolo[4,3-aJquinoxalin-1-one),β-肾上腺素能受体激动荆异丙肾上腺素(Isoprenaline,ISO)和拮抗剂普萘洛尔(Propranolol)对NO作用的影响。结果:①L—Arg抑制小鼠回肠自主收缩幅度,呈浓度依赖性。②L-NNA(3×10^-4mol/L),ODQ(3×10^-4mol/L)均减弱L-Arg的抑制效应。③Propranolol(3×10^-6mol/L)明显减弱L—Arg的抑制效应。④ISCO(1×100mol/L)明显增强L—Arg的抑制效应。而Propranolol(3×10^-6mol/L)和ISCO(1×10^-7mol/L)孵育组,L—Arg的抑制作用无明显变化。结论:L-Arg经NOS催化生成NO后经cGMP途径发挥对小鼠回肠自主收缩的抑制作用,良受体途径也部分参与了NO的作用过程。 相似文献
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Glycosylation of beta(1)-adrenergic receptors regulates receptor surface expression and dimerization
He J Xu J Castleberry AM Lau AG Hall RA 《Biochemical and biophysical research communications》2002,297(3):565-572
The beta(1)-adrenergic receptor (beta(1)AR) has one predicted site of N-linked glycosylation on its extracellular amino-terminus, but the glycosylation and potential functional importance of this site have not yet been examined. We show here that the beta(1)AR is glycosylated in various cell types and that mutation of the single predicted site of N-linked glycosylation (N15A) results in the formation of receptors that are not N-glycosylated. The beta(1)AR N15A mutant exhibited significantly decreased basal surface expression relative to the wild-type receptor but had no detectable deficits in ligand binding or agonist-promoted internalization. Co-immunoprecipitation experiments using Flag-tagged and HA-tagged receptors demonstrated that the beta(1)AR-N15A mutant receptor exhibits a markedly reduced capacity for dimerization relative to wild-type beta(1)AR. These data reveal that the beta(1)AR is glycosylated on Asn15 and that this glycosylation plays a role in regulating beta(1)AR surface expression and dimerization. 相似文献
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Ines Armando Andres P. Lemoine Monica Ferrini Enrique T. Segura Marta Barontini 《Cellular and molecular neurobiology》1989,9(1):115-122
1. The effect of repeated isolation stress on MAO inhibitory activity (tribulin) in rat tissues as well as on plasma catecholamine levels was investigated. 2. Animals were subjected to a daily period of isolation (9 min) and sacrificed on days 1, 2, 4, and 5. 3. In brain and cerebellum the levels of both inhibitory activities were found to be significantly higher in animals sacrificed on days 1-2 than in either controls or animals sacrificed on days 4-5. 4. In heart and kidney the highest levels of both activities were found in animals sacrificed on days 4-5. 5. Plasma levels of dopamine on day 4 were significantly higher than those in controls or in any of the experimental groups. Plasma levels of epinephrine showed step-by-step increments from day 1 up to day 5, reaching statistical significance only on day 5. Plasma levels of norepinephrine were significantly increased on days 2, 4, and 5. 6. Under the experimental conditions of this study, we have shown a rapid and short-lasting increment of tribulin in the central nervous system. Its disappearance on days 4-5 could be related to adaptation to the novel situation. Changes in the peripheral tissues appeared later, and a similar adaptation was absent during the period of observation. 7. Tribulin would be related to the stressful situation not only as an anxiety-promoting agent but also in contributing to the maintenance of high levels of circulating catecholamines. 相似文献
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Recombinant human interleukin-1 receptor antagonist (rHuIL-1ra) was produced in E. coli as an inclusion body. rHuIL-1ra was purified to Over 98% purity by anion exchange chromatography after on-column refolding. The optimized processes produced more than 2 g pure refolded rHuIL-1ra per 1 l culture, corresponding to a 44% recovery, without an intermediate dialysis step. Refolded rHuIL-1ra had full biological activity with the MTT assay. An intramolecular disulfide linkage in the oxidized recombinant protein was suggested by data from HPLC and non-reducing SDS-PAGE. 相似文献
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Receptor activity modifying proteins interaction with human and porcine calcitonin receptor-like receptor (CRLR) in HEK-293 cells 总被引:3,自引:0,他引:3
Aiyar Nambi Disa Jyoti Pullen Mark Nambi Ponnal 《Molecular and cellular biochemistry》2001,224(1-2):123-133
Calcitonin gene-related peptide (CGRP) and adrenomedullin (ADM), two closely related peptides, initiate their biological responses through their interaction with calcitonin receptor-like receptor (CRLR). The CRLR receptor phenotype can be determined by coexpression of CRLR with one of the three-receptor activity modifying proteins (RAMPs). In this report, we characterized the pharmacological properties of the human or porcine CRLR with individual RAMPs transiently expressed in human embroynic kidney cell line (HEK-293). Characterization of RAMP1/human or porcine CRLR combination by radioligand binding ([125I] hCGRP) and functional assay (activation of adenylyl cyclase) revealed the properties of CGRP receptor. Similarly characterization of RAMP2/human or porcine CRLR and RAMP3/human or porcine CRLR combination by radioligand binding ([125I]rADM) and functional assay (activation of adenylyl cyclase) revealed the properties of ADM (22–52) sensitive-ADM receptor. In addition, porcine CRLR/RAMP2 or 3 combination displayed specific high affinity [125I] hCGRP binding also. Also, co-transfection of porcine CRLR with RAMPs provided higher expression level of the receptor than the human counterpart. Thus the present study along with earlier studies strongly support the role of RAMPs in the functional expression of specific CRLRs. 相似文献
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F. Oury-Donat I. A. Lefevre O. Thurneyssen T. Gauthier A. Bordey† P. Feltz† X. Emonds-Alt G. Le Fur P. Soubrie 《Journal of neurochemistry》1994,62(4):1399-1407
The effects of a novel nonpeptide NK1 tachy-kinin receptor antagonist, SR 140333, on the functional consequences of NK1 receptor activation in a human astrocytoma cell line, U373MG, were investigated. Radioligand binding conducted with 125l-Bolton-Hunter substance P revealed a competitive inhibition by SR 140333 and its R enantiomer SR 140603 with Ki values of 0.74 and 7.40 nM, respectively. The NK1-selective agonist, [Sar9,Met(O2)11]-substance P, stimulated the formation of inositol phosphates with an EC50 of 3.8 × 10?9M. SR 140333 blocked the stimulatory effect of this agonist (10?7M) with an IC50 of 1.6 × 10?9M,whereas the effect of another NK1 agonist, septide (EC50= 1.5 × 10?8M)was antagonized with an IC50 of 2.1 × 10?10M.Enhancement of [3H]taurine release by [Sar9,Met(O2)11]-substance P (EC50= 7.4 × 10?9M) was also inhibited by SR 140333 with an IC50 of 1.8 × 10?9 M. SR 140603 was 10-fold less potent than SR 140333 in inhibiting inositol monophosphate formation and [3H]taurine release. The calcium mobilization induced by [Sar9,Met(O2)11]-substance P (10?8M) was totally prevented by 10?8MSR 140333. Patchclamp experiments showed that SR 140333 depressed the outward current evoked by 5 × 10?8M [Sar9, Met(O2)11]-substance P with an IC50 of 1.3 × 10?9M. The expression of c-fos was stimulated by [Sar9,Met(O2)11]-substance P with an EC50 of 2.5 × 10?10M, an effect that was also inhibited by SR 140333 with an IC50 of 1.1 × 10?9M. The present results illustrate the sequential events of the response elicited by NK1 agonists, which were antagonized by SR 140333, demonstrating its powerful NK1 antagonist activity on a functional basis. 相似文献
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Shelley S. Marks Daniel L. Watson Celia L. Carpenter Robert O. Messing David A. Greenberg 《Journal of neurochemistry》1989,53(1):168-172
Treatment with 200 mM ethanol for 6 days increased binding of the Ca2+ channel antagonist, (+)-[3H]PN 200-110, to intact PC12 cells in culture. Enhancement of binding by ethanol was due to an increase in binding site number without appreciable change in binding affinity. Long-term exposure to Ca2+ channel antagonist drugs (nifedipine, verapamil, or diltiazem), which, like ethanol, acutely inhibit Ca2+ flux, failed to alter (+)-[3H]PN 200-110 binding to PC12 membranes. Cotreatment of ethanol-containing cultures with the Ca2+ channel agonist, Bay K 8644, did not attenuate the response to ethanol; instead, chronic exposure to Bay K 8644 alone increased (+)-[3H]PN 200-110 binding. These results suggest that chronic exposure to ethanol increases Ca2+ channel antagonist receptor density in living neural cells, but that acute inhibition of Ca2+ flux by ethanol is unlikely to trigger this response. 相似文献
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Prasad V. Chaturvedula Stephen E. Mercer Sokhom S. Pin George Thalody Cen Xu Charlie M. Conway Deborah Keavy Laura Signor Glenn H. Cantor Neil Mathias Paul Moench Rex Denton Robert Macci Richard Schartman Valerie Whiterock Carl Davis John E. Macor Gene M. Dubowchik 《Bioorganic & medicinal chemistry letters》2013,23(11):3157-3161
Calcitonin gene-related peptide (CGRP) receptor antagonists have been shown to be efficacious as abortive migraine therapeutics with the absence of cardiovascular liabilities that are associated with triptans. Herein, we report the discovery of a highly potent CGRP receptor antagonist, BMS-742413, with the potential to provide rapid onset of action through intranasal delivery. The compound displays excellent aqueous solubility, oxidative stability, and toxicological profile. BMS-742413 has good intranasal bioavailability in the rabbit and shows a robust, dose-dependent inhibition of CGRP-induced increases in marmoset facial blood flow. 相似文献
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《Bioscience, biotechnology, and biochemistry》2013,77(2):554-558
A cDNA encoding a novel heptahelical receptor from the prothoracic glands of the silkworm, Bombyx mori was cloned and sequenced during screening of a prothoracicotropic hormone (PTTH) receptor. Orthologs of this receptor are found not only in insects, but also in the vertebrates. In B. mori, ubiquitous expression of the mRNA was observed in the larva. Also, a higher expression level in the prothoracic glands was observed before molting and metamorphosis and was impaired after pupal molting. But, further analysis is required to confirm whether this receptor cDNA encodes the PTTH receptor. 相似文献
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Peana AT Rubattu P Piga GG Fumagalli S Boatto G Pippia P De Montis MG 《Life sciences》2006,78(21):2471-2474
In recent studies performed in our laboratory we have shown that acute administration of (-)-linalool, the natural occurring enantiomer in essential oils, possesses anti-inflammatory, antihyperalgesic and antinociceptive effects in different animal models. The antihyperalgesic and antinociceptive effects of (-)-linalool have been ascribed to its capacity in stimulating the opioidergic, cholinergic and dopaminergic systems, as well as to its interaction with K+ channels, or to its local anaesthetic activity and/or to the negative modulation of glutamate transmission. Activation of A1 or A2A receptors has been shown to induce antinociceptive effects, and the possible involvement of adenosine in (-)-linalool antinociceptive effect, has not been elucidated yet. Therefore, in the present study, we have investigated the effects of 1,3-dipropyl-8-cyclopentylxanthine (DPCPX), a selective adenosine A1 receptor antagonist and the effects of 3,7-dimethyl-1-propargilxanthine (DMPX), a selective adenosine A2A receptor antagonist on the antinociception of (-)-linalool in mice, measured in the hot-plate test. Both DPCPX (0.1 mg/kg; i.p.) and DMPX (0.1 mg/kg; i.p.) pre-treatment significantly depressed the antinociceptive effect of (-)-linalool at the highest doses tested. These findings demonstrated that the effect of (-)-linalool on pain responses is, at least partially, mediated by the activity of adenosine A1 and A2A receptors. 相似文献