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

许多荷尔蒙和神经递质通过一类被称为B家族G蛋白偶联受体(GPCRs)的蛋白质来发挥作用。这些激素包括与糖尿病和其他代谢疾病有关的激素，如GLP-1和高血糖素，这些激素与糖尿病和其他老年人常见的代谢疾病有关，涉及压力和焦虑的促肾上腺皮质激素释放因子，以及涉及维持骨骼的甲状旁腺激素。众所周知，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。人体各处都有坡道。然而，直到最近，RAMP-受体相互作用的后果仍不清楚。最近对这些B家族GPCRs中的一小部分的研究表明，坡道对功能有重要影响，因此现在是时候将这项研究扩展到所有15个B家族GPCRs。我们已经发现，这可以通过分析人类受体和酵母中RAMP的行为来快速、廉价和容易地实现，我们将使用这种方法来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进行这些相互作用的后果。我们产生的结果将使更复杂的实验得以进行，以确定这些相互作用在体内模型中的生理后果。这一点很重要，因为我们的数据表明，斜坡关联可以从根本上改变单个受体的属性；忽视斜坡影响的实验可能会给人对受体真实功能的误导性印象。此外，斜坡与受体的结合很可能会产生一种可以选择性地被药物靶向的结构。

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.