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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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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 Arg182 in the second extracellular loop of angiotensin II receptor AT2 in ligand binding

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BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 1999年第3期263卷 816-819页

作者： Kurfis, J Knowle, D Pulakat, L Bowling Green State Univ Dept Biol Sci Bowling Green OH 43403 USA

The phenolic side chain of Tyr(4) present in Ang II is proposed to interact with the side chain of Arg 167 of the AT1 receptor. To determine the contribution of the analogous Arg182 in the ligand-binding properties of the AT2, we replaced the Arg182 with Glu and Ala, and analyzed the ligand-binding properties. Our results suggest that replacing Arg182 with either Glu or Ala abolished the ability of the AT2 receptor to bind the nonspecific peptidic ligands, (125)I-Ang II and [(128)I-Sar(1-)Ile(8)]Ang II, as well as the AfI`2 receptor-specific peptidic ligand (125)I-CGP42112A We have shown previously that replacing the positively charged side chain of Lys215 with the negatively charged side chain of Glu in the fifth TMD did not alter the high affinity binding of (125)I-CGP42112A to the AT2 receptor. However, ligand-binding properties of the Arg182Glu mutant suggest that positively charged side chain of Arg182 located in the junction of second ECL and the fourth TMD is critical for high affinity binding of all three peptidic ligands to the AT2 receptor. (C) 1999 Academic Press.

关键词：氨基酸序列氨基酸取代血管紧张素Ⅱ/代谢精氨酸结合部位 DNA引物配体模型分子分子序列数据诱变定点卵母细胞/生理学聚合酶链反应蛋白质结构二级受体血管紧张素 2型受体血管紧张素/化学受体血管紧张素/遗传学受体血管紧张素/代谢重组蛋白质类/化学重组蛋白质类/代谢爪蟾光滑动物女(雌)性大鼠

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Role of the His273 located in the sixth transmembrane domain of the angiotensin II receptor subtype AT2 in ligand-receptor interaction

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BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 1999年第3期257卷 704-707页

作者： Turner, CA Cooper, S Pulakat, L Bowling Green State Univ Dept Sci Biol Bowling Green OH 43403 USA

Angiotensin II receptor subtypes AT1 and AT2 are proteins with seven transmembrane domain (TMD) topology and share 34% homology. It was shown that His256, located in the sixth TMD of the AT1 receptor, is needed for the agonist activation by the Phe8 side chain of angiotensin II, although replacing this residue with arginine or glutamine did not significantly alter the affinity binding of the receptor. We hypothesized that the His273 located in the sixth transmembrane domain of the AT2 receptor may play a similar role in the functions of the AT2 receptor, although this residue was not identified as a conserved residue in the initial homology comparisions. Therefore, we replaced His273 of the AT2 receptor with arginine or glutamine and analyzed the ligand-binding properties of the mutant receptors using Xenopus oocytes as an expression system. Our results suggested that the AT2 receptor mutants His273Arg and His273 Glu have lost their affinity to [(125)I-Sar(1)-Ile(8)]Ang II, a peptidic ligand that binds both the AT1 and AT2 receptors and to (125)I-CGP42112A, a peptidic ligand that binds specifically to the AT2 receptor. Thus, His273 located in the sixth TMD of the AT2 receptor seems to play an important role in determining the binding properties of this receptor. Moreover, these results along with our previous observation that the Lys215 located in the 5th TMD of the AT2 receptor is essential for its high affinity binding to [(125)I-Sar(1)-Ile(8)]Ang II indicate that key amino acids located in the 5th and 6th TMDs of the AT2 receptor are needed for high affinity binding of the AT2 to its ligands. (C) 1999 Academic Press.

关键词：氨基酸取代血管紧张素Ⅱ/类似物和衍生物血管紧张素Ⅱ/代谢结合部位细胞膜/代谢组氨酸/遗传学组氨酸/代谢配体赖氨酸/遗传学赖氨酸/代谢寡肽类/代谢卵母细胞/代谢 RNA 信使/投药和剂量 RNA 信使/遗传学受体血管紧张素 1型受体血管紧张素 2型受体血管紧张素/化学受体血管紧张素/遗传学受体血管紧张素/代谢沙拉新构效关系爪蟾光滑动物大鼠

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Structural analysis of angiotensin IV receptor (AT₄) from selected bovine tissues

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JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS 1999年第2期289卷 1075-1083页

作者： Zhang, JH Hanesworth, JM Sardinia, MF Alt, JA Wright, JW Harding, JW Washington State Univ Dept Vet & Comparat Anat Pharmacol & Physiol Pullman WA 99164 USA

The angiotensin IV receptor (AT(4)) receptor is widely distributed in both species and tissues. This broad distribution appears to be reflected in an equally diverse repertoire of physiological actions that are mediated through AT(4) receptors. This breadth of location and function of AT(4) receptors encourages speculation that multiple AT(4) isoforms might exist. In this study, we compared the structural properties of bovine AT(4) receptors from adrenals, kidney, heart, thymus, bladder, aorta, and hippocampus. These comparisons were made using polyacrylamide gel electrophoresis or HPLC analysis of AT(4) receptors that had been covalently radiolabeled with the AT(4)-specific photoprobe I-125-benzoyl phenylalamine-angiotensin IV. Except for the hippocampal AT(4) receptor, the binding subunit in all tissues had a molecular mass of approximately 165 kDa and associated with additional subunits via disulfide linkages. The hippocampal receptor was significantly smaller (150 kDa) and did not appear to possess other disulfide-linked subunits. The receptor was highly glycosylated in all tissues examined. Peptide mapping following cleavage of I-125-labeled receptor with endopeptidase C or cyanogen bromide resulted in complex cleavage patterns. Together these mapping studies demonstrated the uniqueness of the hippocampal receptor and further suggested that other AT(4) isoforms may exist and be variably distributed among bovine tissues. In agreement with the peptide mapping studies, differences in the binding pattern of several AngIV analogs were observed among the various tissues.

关键词：血管紧张素Ⅱ/类似物和衍生物血管紧张素Ⅱ/化学色谱法高压液相电泳聚丙烯酰氨凝胶糖基化配体膜分子量器官特异性受体血管紧张素/化学动物牛

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