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年在肌肉中发现了5-三磷酸腺苷（ATP），很快就意识到它是细胞内能量生产的关键。但是，就像通常情况下一样，同一分子在细胞外部具有重要作用，并用于在细胞之间发出信号。 ATP的细胞表面受体（称为P2X受体）是中间有一个孔的蛋白质：当ATP与受体结合时，它们充当门，使小离子越过膜。这反过来导致细胞行为的变化。实际上，现在已经知道，这些对ATP的反应调节哺乳动物的多种生理过程，包括味道，膀胱排空，氧气感觉，炎症和疼痛。因此，P2X受体的ATP信号传导代表了涉及疼痛和炎症的疾病的新靶标。要了解P2X受体的工作原理，重要的是要了解它们的调节方式，并发现P2X受体活性的进一步影响。但是，由于在适合实验室研究的简单模型生物中未发现P2X受体，因此很难进行此类研究。最近，我们发现P2X受体存在于dictyostelium discoideum中。 Dictyostelium用于研究细胞和发育生物学中的许多过程，因为其相对简单性以及可以对遗传和生化研究的轻松进行。我们惊讶地发现，一个dictyostelium p2x受体实际上调节了对ATP内部细胞内部的反应，而不是在细胞表面。但是我们认为，这种作用与能量代谢无关：相反，细胞需要适应被浸入水中的压力所必需的受体。由于柱状细胞通常生活在土壤中，因此这可能是其生存的重要适应性。最重要的是，这些发现将使我们能够解决如何调节P2X功能。首先，我们将使用尖端的遗传和生化技术来识别调节dictyostelium中受体活性所需的其他蛋白质。其次，我们将确定其他四个P2X受体的作用，并比较这些受体与哺乳动物P2X受体所看到的ATP反应。由于P2X受体的运行基本机制是从Amoeba到MAN的基本机制，我们将能够促进我们对P2X受体功能，调节和结构中所有动物种类的理解。