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首页> 外文期刊>Canadian Journal of Physiology and Pharmacology >Interaction of a non-peptide agonist with angiotensin II AT1 receptor mutants.
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Interaction of a non-peptide agonist with angiotensin II AT1 receptor mutants.

机译：非肽激动剂与血管紧张素II AT1受体突变体的相互作用。

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摘要

To identify residues of the rat AT1A angiotensin II receptor involved with signal transduction and binding of the non-peptide agonist L-162,313 (5,7-dimethyl-2-ethyl-3-[[4-[2(n-butyloxycarbonylsulfonamido)-5-isobutyl-3 -thienyl]phenyl]methyl]imidazol[4,5,6]-pyridine) we have performed ligand binding and inositol phosphate turnover assays in COS-7 cells transiently transfected with the wild-type and mutant forms of the receptor. Mutant receptors bore modifications in the extracellular region: T88H, Y92H, G1961, G196W, and D278E. Compound L-162,313 displaced [125I]-Sar1,Leu8-AngII from the mutants G196I and G196W with IC50 values similar to that of the wild-type. The affinity was, however, slightly affected by the D278E mutation and more significantly by the T88H and Y92H mutations. In inositol phosphate turnover assays, the ability of L-162,313 to trigger the activation cascade was compared with that of angiotensin II. These assays showed that the G196W mutant reached a relative maximum activation exceeding that of the wild-type receptor; the efficacy was slightly reduced in the G1961 mutant and further reduced in the T88H, Y92H, and D278E mutants. Our data suggest that residues of the extracellular domain of the AT1 receptor are involved in the binding of the non-peptide ligand, or in a general receptor activation phenomenon that involves conformational modifications for a preferential binding of agonists or antagonists.
机译：鉴定大鼠AT1A血管紧张素II受体的残基，涉及信号转导和非肽激动剂L-162,313（5,7-二甲基-2-乙基-3-[[4- [2（n-丁氧基羰基磺酰胺基） 5-异丁基-3-噻吩基]苯基]甲基]咪唑[4,5,6]-吡啶）我们已经在野生型和突变型瞬时转染的COS-7细胞中进行了配体结合和肌醇磷酸转换实验受体。突变受体在胞外区域具有修饰：T88H，Y92H，G1961，G196W和D278E。化合物L-162,313从突变体G196I和G196W取代了​​[125I] -Sar1，Leu8-AngII，其IC50值与野生型相似。但是，亲和力受D278E突变的影响较小，而受T88H和Y92H突变的影响更大。在肌醇磷酸转换试验中，将L-162,313触发激活级联的能力与血管紧张素II的能力进行了比较。这些分析表明，G196W突变体达到的相对最大活化超过野生型受体的活化。功效在G1961突变体中略有降低，在T88H，Y92H和D278E突变体中进一步降低。我们的数据表明，AT1受体胞外域的残基参与非肽配体的结合，或涉及涉及构象修饰以优先结合激动剂或拮抗剂的一般受体活化现象。

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