Characterization of cardiovascular purinoceptors

心血管嘌呤受体的表征

• 批准号: 7437302
• 负责人: TERRANCE M EGAN
• 金额: $ 28.55万
• 依托单位: SAINT LOUIS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-07-01 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7437302
• 关键词: Affect; Binding; Blood Vessels; Calcium ion; Cardiac; Cardiovascular Diseases; Cardiovascular system; Cations; Cell membrane; Cells; Dilated Cardiomyopathy; Endocrine Glands; Event; Family; Family member; Health; Heart; Heart Diseases; Heart failure; Hematopoietic; Hormones; Human; Hypertension; Laboratories; Ligands; Link; Mechanics; Mediating; Membrane; Molecular; Muscle Contraction; Nature; Neuroglia; Neurons; Numbers; P2X-receptor; Patients; Performance; Peripheral; Physiology; Play; Proteins; Public Health; Purinoceptor; Recombinants; Rest; Role; Signal Transduction; Survival Rate; Testing; Tissues; Transgenic Organisms; Work; cell motility; interest; mouse model; novel therapeutics; receptor; research study

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.

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，其利用ATP结合的能量启动阳离子跨细胞膜的去极化通量。钙离子携带不成比例的大部分电流，P2X受体具有所有LGCC家族中最大的Ca2+通量。细胞内Ca2+的升高引起中枢和外周神经元和神经胶质释放递质，促进内分泌腺释放激素，引发肌肉收缩，调节气道纤毛运动，并激活多种细胞中的下游信号级联。ATP对心血管系统有多种作用。造血细胞（P2X7）、血管（P2X0）和心脏（P2X1）。7)所有这些组织都表达P2X受体，并且在许多情况下，ATP对这些组织的作用与Ca2+内流有关。例如，P2X4受体的过表达通过升高静息Ca2+和增强基础心肌收缩力来增强心力衰竭转基因小鼠模型中的心脏性能和心脏存活。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，内源性P2X受体的操纵可能代表用于治疗心脏疾病的新的治疗方法。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+跨膜转运的机制，并了解ATP如何打开孔。在这个建议中，我们概述了实验，建立在我们以前的工作，以提供一个更定量的描述的事件后，ATP结合。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，因为受体可能是一种新的和潜在的令人兴奋的手段，可以提高受许多心血管疾病（包括高血压和心力衰竭）影响的患者的生存率。