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

斜坡在促胰液素样受体配体产生的信号偏差中的作用

基本信息

批准号：
BB/M00015X/1
负责人：
Graham Ladds
金额：
$ 29.66万
依托单位：
University of Warwick
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2015
资助国家：
英国
起止时间：
2015 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=BB%2FM00015X%2F1
关键词：
ROLE RAMPS LIGAND ENGENDERED SIGNAL

项目摘要

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.

许多激素和神经递质通过一类称为B g蛋白偶联受体（GPCR）的蛋白质来执行其功能。这些包括与糖尿病和其他代谢性疾病有关的激素，例如GLP-1和胰高血糖素，在老年人，皮质营养素释放因子中，涉及压力和焦虑症以及甲状旁腺激素，涉及维持骨骼。已知十多年来，这些药物的许多受体可以与称为受体活性修饰蛋白质（坡道）的辅助蛋白相互作用。在整个身体中都发现坡道。然而，直到最近，坡道受体相互作用的后果仍未知。对少数这些家族B GPCR的最新研究表明，坡道对功能具有重要的后果，因此现在及时将这项研究扩展到所有15个家庭B GPCR。我们发现，通过分析酵母中的人体受体和坡道的行为可以快速，便宜，轻松地实现这一目标，我们将使用这种方法来全面探索在人类中发现的所有家庭B GPCR如何受到坡道的影响。我们将扩展研究以确定使用人类细胞的这些相互作用的后果。我们生成的结果将使更复杂的实验能够确定体内模型中这些相互作用的生理后果。这很重要，因为我们的数据表明坡道关联可以从根本上改变单个受体的特性。忽略考虑坡道影响的实验会给受体的真实功能带来误导的印象。此外，坡道与受体的关联很可能会产生可以由药物选择性靶向的结构。

项目成果

期刊论文数量（10）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Discovery of Novel Adenosine Receptor Agonists That Exhibit Subtype Selectivity

发现具有亚型选择性的新型腺苷受体激动剂

DOI：
10.7892/boris.76205
发表时间：
2016
期刊：
影响因子：
0
作者：
Knight A
通讯作者：
Knight A

Receptor Activity-modifying Protein-directed G Protein Signaling Specificity for the Calcitonin Gene-related Peptide Family of Receptors.

DOI：
10.1074/jbc.m116.751362
发表时间：
2016-10-14
期刊：
The Journal of biological chemistry
影响因子：
0
作者：
Weston C;Winfield I;Harris M;Hodgson R;Shah A;Dowell SJ;Mobarec JC;Woodlock DA;Reynolds CA;Poyner DR;Watkins HA;Ladds G
通讯作者：
Ladds G

The effects of RAMPs upon cell signalling