THE ROLE OF RAMPS IN LIGAND-ENGENDERED SIGNAL BIAS OF SECRETIN-LIKE RECEPTORS

许多激素和神经递质通过一类称为家族B G蛋白偶联受体（GPCR）的蛋白质来执行其功能。这些包括激素，如GLP-1和胰高血糖素，它们与糖尿病和其他代谢紊乱有关，尤其是在老年人中常见的，促肾上腺皮质激素释放因子，参与应激和焦虑，以及甲状旁腺激素，参与维持骨骼。10多年来，人们已经知道这些药物的许多受体可以与称为受体活性修饰蛋白（RAMP）的辅助蛋白相互作用。RAMP遍布全身。然而，直到最近，RAMP-受体相互作用的后果仍然未知。最近对少数这些家族B GPCR的研究表明，RAMP对功能具有重要影响，因此现在将这项研究扩展到所有15个家族B GPCR是及时的。我们已经发现，这可以通过分析酵母中人类受体和RAMP的行为快速、廉价和容易地实现，我们将使用这种方法全面探索在人类中发现的所有B家族GPCR如何受到RAMP的影响。我们将扩展我们的研究，以确定使用人类细胞的这些相互作用的后果。我们产生的结果将使更复杂的实验被执行，以确定这些相互作用在体内模型的生理后果。这一点很重要，因为我们的数据表明RAMP缔合可以从根本上改变单个受体的性质;忽略RAMP效应的实验可能会对受体的真实功能产生误导性印象。此外，RAMP与受体的结合可能会产生一种可以被药物选择性靶向的结构。

Many hormones and neurotransmitters perform their function through a class of proteins called family B G protein-coupled receptors (GPCRs). These include hormones such as GLP-1 and glucagon which are relevant to diabetes and other metabolic disorders especially common in the elderly, corticotrophin releasing factor, involved in stress and anxiety and parathyroid hormone, involved in maintaining bones. It has been known for over 10 years that many of the receptors for these agents can interact with accessory proteins called receptor activity modifying proteins (RAMPs). RAMPs are found throughout the body. However, until recently, the consequences of RAMP-receptor interactions remained unknown. Recent studies of a small number of these family B GPCRs has shown that RAMPs have important consequences for function and so it is now timely to extend this study to all 15 family B GPCRs. We have discovered that this can be achieved quickly, cheaply and easily by analysing the behaviour of human receptors and RAMPs in yeast and we will use this method to comprehensively explore how all the family B GPCRs found in humans are influenced by RAMPs. We will extend our studies to determine the consequences of these interactions using human cells. The results we generate will enable more sophisticated experiments to be performed to determine the physiological consequences of these interactions in in-vivo models. This is important as our data indicates that RAMP association can radically change the properties of an individual receptor; experiments that neglect to consider the effects of RAMPs can give misleading impressions of the true function of a receptor. Furthermore, it is likely that the association of the RAMP with a receptor will create a structure that can be selectively targeted by drugs.