G-Protein–Coupled Receptor MrgD Is a Receptor for Angiotensin-(1–7) Involving Adenylyl Cyclase, cAMP, and Phosphokinase A
G-Protein–Coupled Receptor MrgD Is a Receptor for Angiotensin-(1–7) Involving Adenylyl Cyclase, cAMP, and Phosphokinase A
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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
DOI：
10.1161/hypertensionaha.116.07572
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发表时间：
2016
期刊：
影响因子：
8.3
通讯作者：
Walther T
中科院分区：
文献类型：
--
作者：
Tetzner;Gebolys K;Meinert C;Klein S;Uhlich A;Trebicka J;Villacañas Pérez O;Walther T
血管紧张素 (Ang)-(1-7) 具有心血管保护作用，并且是肾素-血管紧张素系统中经常有害的 Ang II 的对手。尽管人们普遍认为G蛋白偶联受体Mas是七肽的受体，但由于缺乏对Ang-(1-7)刺激的初始信号分子的了解，阻碍了配体/受体药理学的明确表征以及进一步假设的七肽受体的鉴定。该研究旨在鉴定 Ang-(1-7) 刺激的第二信使，从而确认和发现七肽受体。 Ang-(1–7) 提高原代细胞（例如内皮细胞或系膜细胞）中的 cAMP 浓度。使用 cAMP 作为受体转染的人胚胎肾 (HEK293) 细胞中的读数，我们提供了药理学证据，证明 Mas 是 Ang-(1–7) 的功能性受体。此外，我们还确定了 G 蛋白偶联受体 MrgD 作为 Ang-(1-7) 的第二个受体。因此，七肽未能增加具有Mas和MrgD遗传缺陷的原代系膜细胞中的cAMP浓度。缺乏MrgD的小鼠在给予Ang-(1-7)后表现出血流动力学反应受损。此外，我们排除了 Ang II 2 型受体作为七肽的受体，但发现 Ang II 2 型阻断剂 PD123319 也可以阻断 Mas 和 MrgD 受体。我们的结果导致肾素-血管紧张素系统的扩展和部分修订，通过识别 Ang-(1-7) 的第二种受体，通过排除 Ang II 2 型作为七肽的受体，并通过强制重新审视仅使用 PD123319 得出 Ang II 2 型功能的出版物。
Angiotensin (Ang)-(1–7) has cardiovascular protective effects and is the opponent of the often detrimental Ang II within the renin–angiotensin system. Although it is well accepted that the G-protein–coupled receptor Mas is a receptor for the heptapeptide, the lack in knowing initial signaling molecules stimulated by Ang-(1–7) prevented definitive characterization of ligand/receptor pharmacology as well as identification of further hypothesized receptors for the heptapeptide. The study aimed to identify a second messenger stimulated by Ang-(1–7) allowing confirmation as well as discovery of the heptapeptide’s receptors. Ang-(1–7) elevates cAMP concentration in primary cells, such as endothelial or mesangial cells. Using cAMP as readout in receptor-transfected human embryonic kidney (HEK293) cells, we provided pharmacological proof that Mas is a functional receptor for Ang-(1–7). Moreover, we identified the G-protein–coupled receptor MrgD as a second receptor for Ang-(1–7). Consequently, the heptapeptide failed to increase cAMP concentration in primary mesangial cells with genetic deficiency in bothMasandMrgD. Mice deficient inMrgDshowed an impaired hemodynamic response after Ang-(1–7) administration. Furthermore, we excluded the Ang II type 2 receptor as a receptor for the heptapeptide but discovered that the Ang II type 2 blocker PD123319 can also block Mas and MrgD receptors. Our results lead to an expansion and partial revision of the renin–angiotensin system, by identifying a second receptor for Ang-(1–7), by excluding Ang II type 2 as a receptor for the heptapeptide, and by enforcing the revisit of such publications which concluded Ang II type 2 function by only using PD123319.
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影响因子：
3.3
作者：
Meinert C;Gembardt F;Böhme I;Tetzner A;Wieland T;Greenberg B;Walther T
通讯作者：
Walther T
影响因子：
8.8
作者：
Klein, Nadine;Gembardt, Florian;Kuebler, Wolfgang M.
通讯作者：
Kuebler, Wolfgang M.
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
影响因子：
4.3
作者：
Gembardt, Florian;Grajewski, Sonja;Walther, Thomas
通讯作者：
Walther, Thomas
DOI：
10.1152/ajpheart.00317.2005
发表时间：
2005-12-01
影响因子：
4.8
作者：
Iwata, M;Cowling, RT;Greenberg, BH
通讯作者：
Greenberg, BH