Kinetics of arrestin interaction with clathrin-coated pits and ubiquitin

人体的完美运行需要识别外部信号并对其做出反应的能力。信号的最初感知是由称为受体的蛋白质完成的。例如，视觉的能力需要人体内的某种对光敏感的装置，并且可以将光转换为适合视觉系统处理的信号。这是通过蛋白质吸收光并将这种吸收转化为化学反应来实现的。因此，这些蛋白质被称为“光受体”。受体在人类中起着非常重要的作用，因为它们不仅需要识别外部信号，而且还需要各个身体部位相互通信。例如，当一个人受到压力时，他的心脏会跳动得更快，血压会上升。这种反应是由大脑释放一种叫做肾上腺素的激素引起的，肾上腺素与身体各部位的受体结合。在心脏中，肾上腺素与肾上腺素受体结合产生一个信号，最终刺激心脏跳动得更快，更有力。这些受体已经被广泛研究，因此，已经开发出许多通过这些受体起作用的药物。事实上，超过30%的药物与这些受体结合。它们中的一些通过打开受体来发挥作用，模仿内源性激素的作用，例如用于治疗哮喘的药物。其他药物阻止激素进入受体，例如治疗高血压的药物。人们可以经常观察到，受体的长期刺激最初导致非常强烈的反应，尽管持续的受体刺激，但该反应随着时间的推移而减弱。例如，用肾上腺素持续刺激心脏最初会使心脏更快，更有力，但即使肾上腺素治疗继续，这种刺激也会逐渐消失。这种效应被称为“脱敏”。脱敏在生物系统中非常频繁地发生，并且通常是期望的，因为它防止系统过度刺激。例如，脱敏使眼睛能够适应非常不同的光水平：在低光水平下，眼睛中的光感受器以全灵敏度工作，而在明亮的光线下，它们会脱敏，灵敏度急剧降低。有些人患有一种罕见的遗传性疾病，其中光受体的脱敏被废除。受影响的人失明是因为他们的眼睛被过度刺激所破坏。然而，有时受体脱敏可能是不希望的，特别是当涉及药物作用时。据信，脱敏通常是由阻止受体产生的信号的传递的蛋白质引起的。这种蛋白质最初是在眼睛中发现的，它介导光受体的脱敏。我们最近已经能够在单个活细胞中显示这种蛋白质与激素受体的结合。在拟议的研究中，我们希望研究这种蛋白质的特性是如何调节的，以及这如何影响受体的脱敏作用。由于受体脱敏对药物治疗有负面影响，因此对其机制的详细了解具有普遍意义。

Flawless operation of the human body requires the ability to recognise external signals and to react to them. The initial sensing of signals is accomplished by proteins called receptors. For example, the ability to see requires some device within the human body that is sensitive to light and can convert light into a signal that is amenable for processing by the visual system. This is accomplished by proteins that absorb light and convert this absorbance into a chemical reaction. These proteins are therefore termed 'light receptors'. Receptors play a very important part in humans since they are not only required for the recognition of external signals but also for the communication of various body parts with each other. For example, when a person is stressed, its heart will beat faster and its blood pressure will rise. This reaction is caused by the release of a hormone called adrenaline from the brain that binds to receptors in various parts of the body. In the heart, binding of adrenaline to adrenaline receptors generates a signal which ultimately stimulates the heart to beat faster and with more power. These receptors have been studied very extensively, and as a result, a number of drugs has been developed that acts through these receptors. In fact, more than 30% of all drugs bind to these receptors. Some of them act by switching the receptor on, mimicking the action of the endogenous hormone, for example drugs for the treatment of asthma. Other drugs block access of the hormone to the receptor, for example drugs for the treatment of high blood pressure. One can frequently observe that long-term stimulation of a receptor leads initially to a very strong reaction that diminishes over time despite continuing receptor stimulation. For example, continuous stimulation of a heart with adrenaline will initially cause the heart to be faster and with more power, but this stimulation will wear off even though the adrenaline treatment is continued. This effect is termed 'desensitisation'. Desensitisation occurs very frequently in biological systems and is often desirable because it prevents a system from overstimulation. For example, desensitisation enables the eye to adapt to very different light levels: at low light levels, the light receptors in the eye operate at full sensitivity whereas in bright light, they are desensitised and their sensitivity is dramatically reduced. Some people suffer from a rare hereditary disease in which the desensitisation of light receptors is abolished. The affected individuals are blind because their eyes are destroyed by overstimulation. However, sometimes receptor desensitisation can be undesirable, especially when the action of drugs is concerned. It is believed that desensitisation is generally caused by a protein that prevents relaying of the receptor-generated signal. This protein was initially discovered in the eye where it mediates the desensitisation of light receptors. We have recently been able to show binding of this protein to hormone receptors in single living cells. In the proposed study, we want to investigate how the properties of this protein are regulated and how this may affect the desensitisation of receptors. Since receptor desensitisation has a negative impact on drug treatment, a detailed understanding of its mechanisms is of general interest.