Molecular characterisation of receptor activity modifying proteins (RAMPs)

维持活细胞的最佳健康和功能，进而维持整个生物体的健康和功能，取决于细胞如何对持续轰炸它们的多种物理和化学刺激做出反应。大多数化学刺激，如激素和神经递质，不是通过直接进入细胞来发挥作用，而是通过与细胞表面称为受体的特定受体蛋白结合来发挥作用。在一类被称为G蛋白偶联受体的受体中，信息传递到细胞内部涉及另一种名为G蛋白的蛋白质。这些受体是最丰富的细胞表面受体类型，构成了目前使用的近50%治疗药物的靶标。因此，了解这些组件是如何工作的是极其重要的。让这一过程变得更加复杂的是，最近发现的另一组新发现的蛋白质，即受体活性修饰蛋白(RAMP)，也在一些系统中发挥着关键作用。我们已经证明，RAMP与许多G蛋白偶联受体相互作用，并且它们具有比以前所理解的更广泛的作用范围。此外，已经证明RAMP-受体界面是药物开发的一个可行的靶点。了解RAMP与G蛋白偶联受体相互作用的程度、它们如何与受体相互作用以及这种相互作用的后果构成了当前提议的基础。这些知识对于解开维持健康、导致疾病的异常以及开发新的治疗方法所涉及的过程至关重要。

The maintenance of optimum health and function of living cells, and consequently that of the whole organism, depends on how cells respond to a multitude of physical and chemical stimuli that continually bombard them. The majority of the chemical stimuli such as hormones and neurotransmitters impart their actions not by directly entering the cell, but instead, by binding to a specific receiver protein at the cell surface called a receptor. In one class of such receptors called G protein-coupled receptors, the transmission of the message to the interior of the cell involves yet another protein called G protein. These receptors are the most abundant type of cell surface receptors and form the targets for nearly 50% of currently used therapeutic drugs. It is, therefore, extremely important to unravel how each of these components works. To make this process even more complex, it was recently shown that another newly discovered group of proteins called receptor activity modifying proteins (RAMPs) too play a critical role in some systems. We have shown that RAMPs interact with many G protein-coupled receptors and that they have a wider range of actions than has previously been appreciated. Moreover, it has been shown that the RAMP-receptor interface is a viable target for drug development. Understanding the extent to which RAMPs interact with G protein-coupled receptors, how they interact with the receptors and the consequences of this interaction forms the basis of the current proposal. Such knowledge is central to the unraveling of the processes involved in the maintenance of health, abnormalities that lead to disease, and in the development of new treatments.