Characterization of cardiovascular purinoceptors

描述(申请人提供)：P2X受体是一个由七个配体门控阳离子通道(LGCC)组成的家族，它们使用ATP结合的能量来启动跨细胞膜的阳离子去极化通量。钙离子携带着不成比例的大比例电流，而P2X受体拥有所有LGCC家族中最大的钙离子流量之一。由此引起的细胞内Ca~(2+)浓度的升高引起中枢、外周神经元和神经胶质细胞释放递质，促进内分泌腺激素的释放，触发肌肉收缩，调节呼吸道纤毛运动，并激活多种细胞中的下游信号级联反应。三磷酸腺苷对心血管系统有多种影响。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钙内流有关。例如，在心力衰竭转基因小鼠模型中，过表达的P2X4受体通过提高静息钙离子和增强基础心肌收缩能力来改善心脏性能和延长存活时间。大自然本身也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。本实验室的研究重点是重组P2X受体的分子生理学研究。我们特别感兴趣的是描述ATP门控的钙离子跨膜转运的机制，并了解ATP是如何打开毛孔的。在这份提案中，我们概述了在我们以前工作的基础上进行的实验，以提供对ATP结合之后的事件的更定量的描述。与公共健康相关：我们的工作具有相关性，因为它提供了更好地了解ATP在健康和疾病中所起作用所需的缺失信息。这一点很重要，因为受体可能提供一种新的、潜在的令人兴奋的方法，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.