Characterization of cardiovascular purinoceptors

描述（由申请人提供）：P2X受体是一个由7个配体门控阳离子通道（lgcc）组成的家族，它们利用ATP结合的能量启动阳离子穿过细胞膜的去极化通量。钙离子携带不成比例的大比例的电流，和P2X受体有最大的钙离子通量的所有LGCC家族之一。由此导致的细胞内Ca2+的升高引起中枢和外周神经元和胶质细胞的递质释放，促进内分泌腺的激素释放，触发肌肉收缩，调节气道纤毛运动，并激活多种细胞中的下游信号级联反应。ATP对心血管系统有多种作用。造血细胞（P2X7）、血管（P2XO）和心脏（P2X!.7）都表达P2X受体，在许多情况下，ATP对这些组织的作用与Ca2+内流有关。例如，P2X4受体的过表达通过提高静息Ca2+和增强心脏基础收缩力来提高心力衰竭转基因小鼠模型的心脏功能和延长生存期。自然界本身可能使用类似的方法，因为P2X受体在患有扩张型心肌病的人类患者的心脏中上调。因此，操纵内源性P2X受体可能是治疗心脏病的一种新的治疗方法。我们实验室的重点是重组P2X受体的分子生理学研究。我们特别感兴趣的是描述ATP门控Ca2+跨膜运输的机制，并了解ATP如何打开孔。在本提案中，我们概述了建立在我们以前的工作基础上的实验，以提供ATP结合后事件的更定量描述。与公共卫生的相关性：我们的工作是相关的，因为它提供了更好地理解ATP在健康和疾病中所起作用所需的缺失信息。这是很重要的，因为受体可能提供一种新的和潜在的令人兴奋的方法来提高受包括高血压和心力衰竭在内的许多心血管疾病影响的患者的存活率。

DESCRIPTION (provided by applicant): P2X receptors are a family of seven ligand-gated cation channels (LGCCs) that use the energy of ATP binding to initiate a depolarizing flux of cations across cell membranes. Calcium ions carry a disproportionately large percentage of this current, and P2X receptors have one of the largest Ca2+ fluxes of all LGCC families. The resulting rise in intracellular Ca2+ evokes transmitter release from central and peripheral neurons and glia, promotes hormone release from endocrine glands, triggers contraction of muscle, regulates airway ciliary motility, and activates downstream signaling cascades in a variety of cells. ATP has multiple effects on the cardiovascular system. Hematopoietic cells (P2X7), blood vessels (P2XO, and the heart (P2X!.7) all express P2X receptors, and in many cases, the actions of ATP on these tissues are linked to Ca2+ influx. For example, over-expression of the P2X4 receptor enhances cardiac performance and prolongs survival in a transgenic mouse model of heart failure by elevating resting Ca2+ and enhancing basal cardiac contractility. Nature itself may use a similar approach, as P2X receptors are upregulated in the hearts of human patients suffering from dilated cardiomyopathy. Manipulation of endogenous P2X receptors may therefore represent a new therapeutic approach for the treatment of cardiac disease. The focus of our laboratory is the study of the molecular physiology of recombinant P2X receptors. We are particularly interested in describing the mechanics of ATP-gated Ca2+ transport across the membrane and understanding how ATP opens the pore. In this proposal, we outline experiments that build upon our previous work to provide a more quantitative description of the events that follow ATP binding. Relevance to public health: Our work is relevant because it provides the missing information needed to better understand the role that ATP plays in health and sickness. This is important because the receptors may present a new and potentially exciting means of increasing the rate of survival of patients affected by a number of cardiovascular diseases including hypertension and heart failure.