Arresting type 1 angiotensin receptors

当血压（或血液中的盐分）降低时，我们的身体会产生一种叫做血管紧张素II的激素。这种激素通过使血管收缩、使我们口渴、通过对肾脏的影响引起盐和液体潴留来增加血压。在一些心血管疾病中，血管紧张素II的产生或我们对这种激素的敏感性升高。因此，我们了解血管紧张素II是如何起作用的，以及它在体内的作用是如何介导的，这是至关重要的。为了使血管紧张素II发挥作用，它必须首先与受体结合。受体是蛋白质，像锁一样由激素钥匙打开。因此，血管紧张素II的细胞受体参与和激活血管紧张素II在我们血液中的增加。然后这些受体产生信号，引发反应（例如血管收缩）。随后，受体被关闭以防止过度刺激。在本应用中提出的实验将继续我们对血管紧张素II受体如何被调节或开关的研究。受体关闭的一个主要方式是通过一种被称为磷酸化的修饰来标记它们。这些修饰过的受体随后与称为阻滞蛋白的蛋白质结合，正如其名称所示，阻滞蛋白在阻止进一步的受体信号传导方面发挥作用。这些抑制也有助于将活化的受体从细胞表面移到细胞内部。抑制因子如何与受体相互作用并调节其功能尚不清楚。该应用程序提出了实验来研究与血管紧张素II受体相关的抑制素作用的分子机制。这些研究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.