Kinetics of arrestin interaction with clathrin-coated pits and ubiquitin

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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.