Decarboxylation of Ang‐(1–7) to Ala1‐Ang‐(1–7) leads to significant changes in pharmacodynamics
Decarboxylation of Ang‐(1–7) to Ala1‐Ang‐(1–7) leads to significant changes in pharmacodynamics
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Angâ(1â7) 脱羧为 Ala1âAngâ(1â7) 导致药效学发生显着变化
DOI：
10.1016/j.ejphar.2018.05.031
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发表时间：
2018
影响因子：
5
通讯作者：
Walther T
中科院分区：
文献类型：
--
作者：
Tetzner A;Naughton M;Gebolys K;Eichhorst J;Sala E;Villacañas O;Walther T
七肽血管紧张素(Ang)-(1-7)是肾素-血管紧张素系统有益臂的一部分。Ang-(1-7)具有心血管保护作用，刺激再生，并反对AngII的有害影响。我们最近确定了G蛋白偶联受体Mas和MrgD作为七肽的受体。Ala1-Ang-(1-7) （Alamandine）是Ang-(1-7)的脱羧形式，具有类似的血管松弛作用，但已被描述为仅刺激MrgD。因此，本研究旨在描述氨基酸1中缺乏羧基对细胞内信号传导的影响，并确定Ala1-Ang-的受体指纹图谱（1 - 7）。在原代内皮细胞和系膜细胞中，Ala1-Ang-(1-7)升高cAMP浓度。Ang-(1-7)和Ala1-Ang-(1-7)产生的剂量反应曲线存在显著差异，其中Ala1-Ang-(1-7)的ec50要低得多，呈钟形曲线。我们提供了药理学证据，证明Mas和MrgD都是Ala1-Ang-的功能性受体（1-7）。因此，在两种受体基因缺失的原代系膜细胞中，七肽不能增加cAMP浓度。正如我们之前对Ang-(1-7)的描述，在Mas/ mrgd转染的HEK293细胞和原代细胞中，Ala1-Ang-(1-7)介导的cAMP增加被AT2受体阻滞剂PD123319阻断。这两种七肽非常不同的剂量-响应曲线可以用硅模型、静电电位计算和Galpha参与高浓度的Ala1-Ang-(1-7)来解释。我们的研究结果确定了Ala1-Ang-(1-7)是一种具有特定药效学特性的肽，并为设计更有效的Ang-(1-7)类似物用于治疗越来越多的疾病奠定了基础。
The heptapeptide angiotensin (Ang)-(1–7) is part of the beneficial arm of the renin-angiotensin system. Ang-(1–7) has cardiovascular protective effects, stimulates regeneration, and opposes the often detrimental effects of AngII. We recently identified the G protein-coupled receptors Mas and MrgD as receptors for the heptapeptide. Ala1-Ang-(1–7) (Alamandine), a decarboxylated form of Ang-(1–7), has similar vasorelaxant effects, but has been described as only stimulating MrgD. Therefore, this study aimed to characterise the consequences of the lack of the carboxyl group in amino acid 1 on intracellular signalling and to identify the receptor fingerprint for Ala1-Ang-(1–7).In primary endothelial and mesangial cells, Ala1-Ang-(1–7) elevated cAMP concentration. Dose response curves generated with Ang-(1–7) and Ala1-Ang-(1–7) significantly differed from each other, with a much lower EC50and a bell-shape curve for Ala1-Ang-(1–7). We provided pharmacological proof that both, Mas and MrgD, are functional receptors for Ala1-Ang-(1–7). Consequently, in primary mesangial cells with genetic deficiency in both receptors, the heptapeptide failed to increase cAMP concentration. As we previously described for Ang-(1–7), the Ala1-Ang-(1–7)-mediated cAMP increase in Mas/MrgD-transfected HEK293 cells and primary cells was blocked by the AT2 receptor blocker, PD123319. The very distinct dose-response curves for both heptapeptides could be explained byin silicomodelling, electrostatic potential calculations, and an involvement of Galpha ifor higher concentrations of Ala1-Ang-(1–7).Our results identify Ala1-Ang-(1–7) as a peptide with specific pharmacodynamic properties and builds the basis for the design of more potent and efficient Ang-(1–7) analogues for therapeutic intervention in a rapidly growing number of diseases.
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DOI：
10.1073/pnas.1432869100
发表时间：
2003-07-08
影响因子：
11.1
作者：
Santos, RAS;Silva, ACSE;Walther, T
通讯作者：
Walther, T
苏拉明类似物作为亚型选择性 G 蛋白抑制剂。
影响因子：
3.6
作者：
Michael Freissmuth;Stefan Boehm;W. Beindl;Peter Nickel;A. P. IJzerman;Martin Hohenegger;C. Nanoff
通讯作者：
C. Nanoff
新型血管紧张素 A 肽的升压和肾血流动力学效应依赖于血管紧张素 II 1A 型受体
影响因子：
8.3
作者：
Rui Yang;I. Smolders;P. Vanderheyden;H. Demaegdt;A. Van Eeckhaut;G. Vauquelin;Aneta Lukaszuk;D. Tourwé;S. Chai;A. Albiston;C. Nahmias;T. Walther;A. Dupont
通讯作者：
A. Dupont
G-蛋白â偶联受体 MrgD 是血管紧张素-(1â7) 的受体，涉及腺苷酸环化酶、cAMP 和磷酸激酶 A
影响因子：
8.3
作者：
Tetzner;Gebolys K;Meinert C;Klein S;Uhlich A;Trebicka J;Villacañas Pérez O;Walther T
通讯作者：
Walther T
影响因子：
7.3
作者：
Beyermann, M.;Heinrich, N.;Berger, H.
通讯作者：
Berger, H.