P2X receptors for ATP: using the model organism Dictyostelium discoideum to understand their regulation and roles

ATP 的 P2X 受体：使用模式生物盘基网柄菌了解其调节和作用

• 批准号: G0900069/1
• 负责人: Christopher Thompson
• 金额: $ 77.5万
• 依托单位: University of Manchester
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2010
• 资助国家: 英国
• 起止时间: 2010 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=G0900069%2F1
• 关键词: P2X; receptors; ATP; using; model

Adenosine 5 -triphosphate (ATP) was discovered in muscles in 1929, and it was soon realised to be the key for energy production inside cells. But, as is often the case, the same molecule has an important role outside cells and is used to signal between cells. The cell surface receptors for ATP, known as P2X receptors, are proteins with a hole down the middle: they acts as gates that allow small ions to cross the membrane when ATP binds to the receptor. This in turn leads to changes in cell behaviour. In fact, it is now known that these responses to ATP regulate diverse physiological processes in mammals, including taste, bladder emptying, oxygen sensation, inflammation and pain. ATP signaling by P2X receptors therefore represents a novel target for disease involving pain and inflammation. To understand how P2X receptors work, it is important to understand how they are regulated, and to discover the further effects of P2X receptor activity. But such studies have been difficult to perform because P2X receptors had not been found in simple model organisms suitable for laboratory studies. Recently, we discovered that P2X receptors are present in the social amoebae, Dictyostelium discoideum. Dictyostelium is used to study many processes in cell and developmental biology, due to its relative simplicity and the ease with which genetic and biochemical studies can be carried out. We were surprised to find that one Dictyostelium P2X receptor actually regulates responses to ATP inside cells, rather than at the cell surface. But we believe that this action is not related to energy metabolism: rather, the receptors are required for the cells to adapt to the stress of being submerged in water. As Dictyostelium cells normally live in the soil, this is likely an important adaptation for their survival. Most importantly, these findings will allow us to address how P2X function is regulated. Firstly, we will use cutting edge genetic and biochemical techniques to identify other proteins that are required to regulate receptor activity in Dictyostelium. Secondly, we will determine the role of the other four P2X receptors and compare the ATP responses of these receptors to those seen with mammalian P2X receptors.Since the basic mechanism of operation of P2X receptors is conserved from amoeba to man, we will be able to advance our understanding of P2X receptor function, regulation and structure in all animal species.

1929年，人们在肌肉中发现了5 -三磷酸腺苷（ATP），并很快意识到它是细胞内能量产生的关键。但是，正如通常情况下，相同的分子在细胞外具有重要作用，并用于细胞之间的信号传递。ATP的细胞表面受体，称为P2 X受体，是中间有一个孔的蛋白质：当ATP结合到受体时，它们作为门允许小离子穿过膜。这反过来又会导致细胞行为的变化。事实上，现在已知这些对ATP的反应调节哺乳动物的多种生理过程，包括味觉、膀胱排空、氧感、炎症和疼痛。因此，通过P2 X受体的ATP信号传导代表了涉及疼痛和炎症的疾病的新靶点。要了解P2 X受体如何工作，重要的是要了解它们是如何调节的，并发现P2 X受体活性的进一步影响。但是这样的研究很难进行，因为在适合实验室研究的简单模式生物中还没有发现P2 X受体。最近，我们发现P2 X受体存在于社会变形虫，盘基网骨藻。由于其相对简单且易于进行遗传和生物化学研究，网囊藻被用于研究细胞和发育生物学中的许多过程。我们惊讶地发现，一种网骨藻P2 X受体实际上调节细胞内对ATP的反应，而不是在细胞表面。但我们认为，这一行动与能量代谢无关：相反，受体是细胞适应淹没在水中的压力所必需的。由于网骨藻细胞通常生活在土壤中，这可能是它们生存的重要适应。最重要的是，这些发现将使我们能够解决P2 X功能是如何调节的。首先，我们将使用最先进的遗传和生物化学技术来确定其他蛋白质所需的调节受体活性的网骨藻。其次，我们将确定其他四种P2 X受体的作用，并将这些受体的ATP反应与哺乳动物P2 X受体的ATP反应进行比较。由于P2 X受体的基本运作机制从阿米巴到人类都是保守的，我们将能够推进我们对所有动物物种中P2 X受体功能，调节和结构的理解。