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

三磷酸腺苷(ATP)于1929年在肌肉中被发现，很快人们就意识到它是细胞内能量产生的关键。但是，就像通常的情况一样，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。细胞表面的ATP受体被称为P2X受体，是一种中间有洞的蛋白质：当ATP与受体结合时，它们充当大门，允许小离子穿过细胞膜。这反过来又会导致细胞行为的变化。事实上，现在已经知道，这些对ATP的反应调节哺乳动物的各种生理过程，包括味觉、膀胱排空、氧气感觉、炎症和疼痛。因此，通过P2X受体传递的ATP信号代表了疼痛和炎症相关疾病的新靶点。要了解P2X受体是如何工作的，重要的是要了解它们是如何被调控的，并发现P2X受体活性的进一步影响。但这样的研究一直很难进行，因为在适合实验室研究的简单模型生物中还没有发现P2X受体。最近，我们发现在社会阿米巴--盘基网托体中存在着P2X受体。网柄网柄菌因其相对简单和易于进行遗传和生化研究而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Dictyostelialp2X受体实际上是在细胞内调节对ATP的反应，而不是在细胞表面。但我们认为，这种作用与能量代谢无关：相反，细胞需要受体来适应淹没在水中的压力。由于网柄苔藓细胞通常生活在土壤中，这可能是它们生存的一种重要适应。最重要的是，这些发现将使我们能够解决P2X功能是如何调控的。首先，我们将使用尖端的遗传和生化技术来确定其他蛋白质，这些蛋白质是调节网柄基菌受体活性所必需的。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受体的ATP反应。由于P2X受体的基本工作机制从阿米巴到人类是保守的，我们将能够促进我们对所有动物物种中P2X受体的功能、调节和结构的理解。

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.