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Agonist-induced phosphorylation of the angiotensin II (AT_1A) receptor requires generation of a conformation that is distinct from the inositol phosphate-signaling state

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JOURNAL OF BIOLOGICAL CHEMISTRY 2000年第4期275卷 2893-2900页

作者： Thomas, WG Qian, HW Chang, CS Karnik, S Baker Med Res Inst Mol Endocrinol Lab Melbourne Vic 8008 Australia Cleveland Clin Fdn Lerner Res Inst Dept Mol Cardiol Cleveland OH 44195 USA

G protein coupled receptors are thought to isomerize between distinct inactive and active conformations, an idea supported by receptor mutations that induce constitutive (agonist-independent) activation. The agonist-promoted active state initiates signaling and, presumably, is then phosphorylated and internalized to terminate the signal. In this study, we examined the phosphorylation and internalization of wild type and constitutively active mutants (N111A and N111G) of the type 1 (AT(1A)) angiotensin II receptor. Cells expressing these receptors were stimulated with angiotensin II (Ang-II) and [Sar(1),Ile(4),Ile(8)]AngII, an analog that only activates signaling through the constitutive receptors, Wild type AT(1A) receptors displayed a basal level of phosphorylation, which was stimulated by AngII, Unexpectedly, the constitutively active AT(1A) receptors did not exhibit an increase in basal phosphorylation nor was phosphorylation enhanced by AngII stimulation. Phosphorylation of the constitutively active receptors was unaffected by pretreatment with the non-peptide AT(1A) receptor inverse agonist, EXP3174, and was not stimulated by the selective ligand, [Sar(1),Ile(4),Ile(8)]AngII. Paradoxically, [Sar(1),Ile(4),Ile(8)]AngII produced a robust (similar to 85% of AngII), dose-dependent phosphorylation of the wild type AT(1A) receptor at sites in the carboxyl terminus similar to those phosphorylated by AngII, Moreover, internalization of both wild type and constitutive receptors was induced by AngII, but not [Sar(1),Ile(4),Ile(8)]AngII, providing a differentiation between the phosphorylated and internalized states. These data suggest that the AT(1A) receptor can attain a conformation for phosphorylation without going through the conformation required for inositol phosphate signaling and provide evidence for a transition of the receptor through multiple states, each associated with separate stages of receptor activation and regulation. Separate transition states may be a

关键词：氨基酸序列血管紧张素Ⅱ/类似物和衍生物血管紧张素Ⅱ/代谢血管紧张素Ⅱ/药理学 CHO细胞仓鼠亚科胞吞作用肌醇磷酸类/代谢磷酰化蛋白质构象受体血管紧张素/激动剂受体血管紧张素/化学受体血管紧张素/代谢信号传导动物

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Role of aromaticity of agonist switches of angiotensin II in the activation of the AT₁ receptor

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JOURNAL OF BIOLOGICAL CHEMISTRY 1999年第11期274卷 7103-7110页

作者： Miura, S Feng, YH Husain, A Karnik, SS Cleveland Clin Fdn Lerner Res Inst Dept Mol Cardiol Cleveland OH 44195 USA

We have shown previously that the octapeptide angiotensin II (Ang II) activates the AT, receptor through an induced-fit mechanism (Noda, K,, Feng, Y. H., Liu, X. P., Saad, Y,, Husain, A., and Karnik, S, S. (1996) Biochemistry 35, 16435-16442). In this activation process, interactions between Tyr(4) and Phe(8) of Ang II with Asn(111) and His(256) Of the AT(1) receptor, respectively, are essential for agonism, Here we show that aromaticity, primarily, and size, secondarily, of the Tyr(4) side chain are important in activating the receptor. Activation analysis of AT(1) receptor position 111 mutants by various Ang II position 4 analogues suggests that an amino-aromatic bonding interaction operates between the residue Asn(111) of the AT(1) receptor and Ty(r)4 of Ang II. Degree and potency of AT(1) receptor activation by Ang II can be recreated by a reciprocal exchange of aromatic and amide groups between positions 4 and 111 of Ang II and the AT(1) receptor, respectively. In several other bonding combinations, set up between Ang II position 4 analogues and receptor mutants, the gain of affinity is not accompanied by gain of function, Activation analysis of position 256 receptor mutants by Ang II position 8 analogues suggests that aromaticity of Phe(8) and His256 Side chains is crucial for receptor activation;however, a stacked rather than an amino-aromatic interaction appears to operate at this switch locus. Interaction between these residues, unlike the Tyr(4):Asn(111) interaction, plays an insignificant role in ligand docking.

关键词：血管紧张素Ⅰ/代谢血管紧张素Ⅱ/激动剂血管紧张素Ⅱ/类似物和衍生物血管紧张素Ⅱ/化学 COS细胞苯丙氨酸/化学受体血管紧张素/激动剂受体血管紧张素/代谢酪氨酸/化学动物

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Activation of the AT₁ angiotensin receptor is dependent on adjacent apolar residues in the carboxyl terminus of the third cytoplasmic loop

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JOURNAL OF BIOLOGICAL CHEMISTRY 2000年第21期275卷 15782-15788页

作者： Zhang, M Zhao, X Chen, HC Catt, KJ Hunyady, L Semmelweis Univ Sch Med Dept Physiol H-1444 Budapest Hungary NICHD Endocrinol & Reprod Res Branch NIH Bethesda MD 20892 USA

The C-terminal region of the third intracellular loop of the AT(1) angiotensin receptor (AT(1)-R) is an important determinant of G protein coupling. The roles of individual residues in agonist-induced activation of G(q/11)-dependent phosphoinositide hydrolysis were determined by mutational analysis of the amino acids in this region. Functional studies on mutant receptors transiently expressed in COS-7 cells showed that alanine substitutions of the amino acids in positions 232-240 of the third loop had no major effect on signal generation. However, deletion mutations that removed Ile(238) or affected its position relative to transmembrane helix VI significantly impaired angiotensin II-induced inositol phosphate responses. Substitution of Ile(238) with an acidic residue abolished the ability of the receptor to mediate inositol phosphate production, whereas its replacement with basic or polar residues reduced the amplitude of inositol phosphate responses. Substitutions of Phe(239) with polar residues had relatively minor effects on inositol phosphate signal generation, but its replacement by aspartic acid reduced, and by positively charged residues (Lys, Arg) significantly increased, angiotensin II-induced inositol phosphate responses. The internalization kinetics of the Ile(238) and Phe239 mutant receptors were impaired in parallel with the reduction in their signaling responses. These findings have identified Ile238 and Phe239 as the critical residues in the C-terminal region of the third intracellular loop of the AT(1)-R for receptor activation. They also suggest that an apolar amino acid corresponding to Ile(238) of the AT(1)-R is a general requirement for activation of other G protein-coupled receptors by their agonist ligands.

关键词：血管紧张素Ⅱ/药理学 COS细胞 GTP结合蛋白质类/代谢肌醇磷酸类/代谢动力学膜蛋白质类/化学膜蛋白质类/遗传学突变蛋白质结合受体血管紧张素 1型受体血管紧张素 2型受体血管紧张素/激动剂受体血管紧张素/化学受体血管紧张素/遗传学信号传导/遗传学转染动物大鼠

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Angiotensin-II subtype 2 receptor agonist (CGP-42112) inhibits catecholamine biosynthesis in cultured porcine adrenal medullary chromaffin cells

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BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 2000年第2期272卷 544-550页

作者： Takekoshi, K Ishii, K Isobe, K Nanmoku, T Kawakami, Y Nakai, T Univ Tsukuba Inst Clin Med Dept Clin Pathol Tsukuba Ibaraki 3058575 Japan

Angiotensin II subtype 2 receptor (AT(2)-R) is abundantly expressed in adrenal medullary chromaffin cells. However, the physiological roles of AT(2)-R in chromaffin cells remain to be clarified. Therefore, we investigated the effects of CGP42112 (AT(2)-R agonist) on catecholamine biosynthesis in cultured porcine adrenal medullary cells. We initially confirmed AT(2)-R was predominantly expressed in porcine adrenal medullary cells by [I-125]-Ang II binding studies. CGP42112 (greater than or equal to 1 nM) significantly inhibited cGMP production from the basal value. Tyrosine hydroxylase (TH) is a rate-limiting enzyme in the biosynthesis of catecholamine, and its activity is regulated by both TH-enzyme activity and TH-synthesis. CGP42112 (greater than or equal to 1 nM) significantly inhibited TH-enzyme activity from the basal value. These inhibitory effects of CGP42112 on TH-enzyme activity and-cGMP production were abolished by PD123319 (AT(2)-R antagonist) while CV-11974 (AT(1)-R antagonist) was ineffective. We also tested whether decrease of cGMP is involved in the inhibitory effect of CGP42112 on TH-enzyme activity. Pretreatment of 8-Br-cGMP (membrane-permeable cGMP analogue) prevented the inhibitory effect of CGP 42112 on TH-enzyme activity. Similar to that of TH-enzyme activity, CGP42112 (greater than or equal to 1 nM) significantly reduced TH-mRNA and TH-protein level from the basal value, and these inhibitory effects were abolished by PD123319 but not CV-11974. These findings demonstrate that CGP 42112 reduces both TH-enzyme activity and TH-synthesis and that these inhibitory effects could be mediated by decrease of cGMP production. (C) 2000 Academic Press.

关键词： 8-溴环腺苷一磷酸/药理学肾上腺髓质/细胞学肾上腺髓质/药物作用肾上腺髓质/酶学肾上腺髓质/代谢血管紧张素Ⅱ/拮抗剂和抑制剂血管紧张素Ⅱ/代谢血管紧张素Ⅱ/药理学苯咪唑类/代谢苯咪唑类/药理学结合竞争性儿茶酚胺类/生物合成细胞培养的嗜铬细胞/细胞学嗜铬细胞/药物作用嗜铬细胞/酶学嗜铬细胞/代谢环GMP/类似物和衍生物环GMP/代谢环GMP/药理学剂量效应关系药物酶激活/药物作用酶诱导/药物作用咪唑类/代谢咪唑类/药理学寡肽类/拮抗剂和抑制剂寡肽类/代谢寡肽类/药理学吡啶类/代谢吡啶类/药理学 RNA 信使/遗传学 RNA 信使/代谢受体血管紧张素 1型受体血管紧张素 2型受体血管紧张素/激动剂受体血管紧张素/代谢猪四唑类/代谢四唑类/药理学酪氨酸单氧化酶/遗传学酪氨酸单氧化酶/代谢动物

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Update: Role of the angiotensin type-2 (AT₂) receptor in blood pressure regulation

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Current Hypertension Reports 2000年第2期2卷 198-201页

作者： Carey, Robert M. Wang, Zhi-Qin Siragy, Helmy M. Department of Medicine University of Virginia School of Medicine Charlottesville VA 22908 United States

In the past, virtually all of the physiologic actions of angiotensin II (ANG II) were thought to be mediated by the type-1 ANG II receptor. However, there is now a compelling body of evidence suggesting that the type-2 (AT ₂) receptor is an important regulator of renal function and blood pressure (BP). The AT₂ receptor stimulates a bradykinin (BK)-nitric oxide (NO)-cyclic GMP vasodilator cascade in blood vessels and in the kidney. Recent studies have shown that absence of the AT₂ receptor lends to pressor and natriuretic hypersensitivity to ANG II. Furthermore, there is now excellent evidence that the AT₂ receptor mediates pressure natriuresis. The AT₂ receptor also stimulates the conversion of prostaglandin E₂ (PGE₂) to PGF₂. In addition, it is now apparent that the therapeutic reduction in BP with AT₁ receptor blockade (eg, losartan, valsartan, candesartan) is mediated by ANG II stimulation of the AT₂ receptor, leading to increased levels of BK, NO, and cGMP. Current evidence predicts that AT₂ receptor agonists would be beneficial in the treatment of hypertension. Copyright © 2000 by Current Science Inc.

关键词：血管紧张素Ⅱ/生理学血压/生理学缓激肽/代谢环GMP/代谢钠尿增多/生理学一氧化氮/代谢受体血管紧张素/激动剂受体血管紧张素/拮抗剂和抑制剂受体血管紧张素/生理学动物人类

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Homologous and heterologous phosphorylation of the AT₂ angiotensin receptor by protein kinase C

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MOLECULAR PHARMACOLOGY 2000年第5期58卷 1156-1161页

作者： Olivares-Reyes, JA Jayadev, S Hunyady, L Catt, KJ Smith, RD NICHHD Endocrinol & Reprod Res Branch NIH Bethesda MD 20892 USA Semmelweis Univ Dept Physiol H-1085 Budapest Hungary

The angiotensin AT(2) receptor is an atypical seven transmembrane domain receptor that is coupled to activation of tyrosine phosphatase and inhibition of MAP kinase, and does not undergo agonist-induced internalization. An investigation of the occurrence and nature of AT(2) receptor phosphorylation revealed that phorbol ester-induced activation of protein kinase C (PKC) in HA-AT(2) receptor-expressing COS-7 cells caused rapid and specific phosphorylation of a single residue (Ser(354))located in the cytoplasmic tail of the receptor. Agonist activation of AT(2) receptors by angiotensin II (Ang II) also caused rapid PKC-dependent phosphorylation of Ser(354) that was prevented by the AT(2) antagonist, PD123177, and by inhibitors of PKC. In cells coexpressing AT(1) and AT(2) receptors, Ang II-induced phosphorylation of the AT(2) receptor was reduced by either PD123177 or the AT(1) receptor antagonist, DuP753, and was abolished by treatment with both antagonists or with PKC inhibitors. These findings indicate that the AT(2) receptor is rapidly phosphorylated via PKC during homologous activation by Ang II, and also undergoes heterologous PKC-dependent phosphorylation during activation of the AT(1) receptor. The latter process may regulate the counteracting effects of AT(2) receptors on growth responses to AT(1) receptor activation.

关键词： COS细胞糖基化寡肽类/药理学磷酰化/药物作用蛋白激酶C/代谢受体血管紧张素 1型受体血管紧张素 2型受体血管紧张素/激动剂受体血管紧张素/代谢动物大鼠

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