Arresting type 1 angiotensin receptors

我们的身体会产生一种名为血管紧张素II的荷尔蒙，以应对血压(或血液中的盐分)的下降。这种荷尔蒙通过引起血管收缩，使我们口渴，并通过对肾脏的影响而导致盐分和液体滞留，从而增加血压。在一些心血管疾病中，血管紧张素II的生成或我们对这种激素的敏感性升高。因此，我们必须了解血管紧张素II是如何工作的，以及它在体内的作用是如何被调节的。血管紧张素II要发挥作用，首先必须与受体结合。受体是蛋白质，其行为就像由荷尔蒙钥匙打开的锁。因此，血管紧张素II的细胞受体被我们血液中血管紧张素II的增加所激活。这些受体然后产生信号，启动反应(例如血管收缩)。随后，受体被关闭，以防止过度刺激。本申请中提出的实验继续我们对血管紧张素II受体如何调节或开启和关闭的研究。关闭受体的一个主要方法是通过一种被称为磷酸化的修饰来标记它们的耳朵。然后，这些修饰的受体被称为拦阻蛋白的蛋白质结合，正如它们的名字所示，拦阻蛋白在阻止进一步的受体信号传递方面发挥作用。这些抑制素还有助于将激活的受体从细胞表面移至细胞内部。阻滞素是如何与受体相互作用并调节其功能的，人们对此知之甚少。这项申请建议进行实验，以研究arrestin作用的分子机制，因为它与血管紧张素II受体有关。这些研究的结果将进一步加深我们对血管紧张素II受体及其在心血管控制中的作用的理解。

Our bodies generate a hormone called angiotensin II in response to a decrease in blood pressure (or salt in our bloodstream). This hormone increases blood pressure by causing blood vessels to constrict, by making us thirsty, and by inducing salt and fluid retention via an effect on the kidneys. In some cardiovascular diseases, the generation of angiotensin II or our sensitivity to this hormone is elevated. It is therefore crucial that we understand how angiotensin II works and how its actions in the body are mediated. For angiotensin II to act it must first bind to a receptor. Receptors are proteins and behave like locks that are opened by the hormone keys. Thus, cellular receptors for angiotensin II are engaged and activated by increases in angiotensin II in our blood. These receptors then produce signals which initiate a response (e.g. constriction of a blood vessel). Subsequently, the receptors are switched-off to prevent over-stimulation. The experiments proposed in this application continue our investigations into how angiotensin II receptors are regulated or switched-on and -off. A major way for receptors to be turned off is for them to be ear-marked by a modification known as phosphorylation. These modified receptors are then bound by proteins termed arrestins, which as indicated by their name play a role in preventing further receptor signalling. These arrestins also help remove activated receptors from the cell surface to the inside of the cell. How arrestins interact with receptors and regulate their function is poorly understood. This application proposes experiments to investigate the molecular mechanisms of arrestin action as it relates to the angiotensin II receptor. Results from these studies will further our understanding of angiotensin II receptors and their role in cardiovascular control.