Kinetics of arrestin interaction with clathrin-coated pits and ubiquitin

人体的完美运作需要识别外部信号并对其做出反应的能力。最初对信号的感知是由称为受体的蛋白质完成的。例如，看东西的能力需要人体内对光敏感的某种设备，并能将光转换成可由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，因为它们不仅是识别外部信号所必需的，而且还是身体不同部位之间相互交流所必需的。例如，当一个人受到压力时，他的心跳会更快，血压会上升。这种反应是由大脑释放一种名为肾上腺素的激素引起的，这种激素与身体不同部位的受体结合在一起。在心脏，肾上腺素与肾上腺素受体结合会产生一种信号，最终刺激心脏跳动得更快、更有力量。人们对这些受体进行了非常广泛的研究，因此，已经开发了一些通过这些受体发挥作用的药物。事实上，超过30%的药物与这些受体结合。其中一些药物通过启动受体来发挥作用，模仿内源性激素的作用，例如治疗哮喘的药物。其他药物阻止荷尔蒙进入受体，例如治疗高血压的药物。人们经常可以观察到，受体的长期刺激最初会导致非常强烈的反应，但随着时间的推移，这种反应会随着时间的推移而减弱，尽管受体持续刺激。例如，用肾上腺素持续刺激心脏，最初会使心脏更快、更有力量，但即使继续肾上腺素治疗，这种刺激也会消失。这种效应被称为“脱敏”。脱敏在生物系统中经常发生，通常是可取的，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：在弱光下，眼睛中的光感受器以完全敏感的方式工作，而在强光下，它们失去敏感性，其敏感度显著降低。一些人患有一种罕见的遗传性疾病，在这种疾病中，光感受器的脱敏被取消。受影响的人是盲人，因为他们的眼睛被过度刺激摧毁了。然而，有时受体脱敏是不可取的，特别是当涉及到药物的作用时。人们认为，脱敏通常是由一种蛋白质引起的，这种蛋白质阻止了受体产生的信号的传递。这种蛋白质最初是在眼睛中发现的，在那里它介导了光感受器的脱敏。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。在这项拟议的研究中，我们想要研究这种蛋白质的性质是如何调节的，以及这可能如何影响受体的脱敏。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是普遍感兴趣的。

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.