CARDIAC PURINOCEPTORS

心脏嘌呤感受器

• 批准号: 6030740
• 负责人: TERRANCE M EGAN
• 金额: $ 17.55万
• 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 2001-04-04
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6030740
• 关键词: adenosine triphosphate; animal genetic material tag; calcium ion; complementary DNA; laboratory rat; myocardium; protein structure function; purinergic receptor; purines; recombinant proteins; site directed mutagenesis; tissue /cell culture; zinc

Fine tuning of cardiac function requires a method of controlling heart rate and contractility in a beat-to-beat fashion. Activation of purinergic P2X receptors may accomplish this objective. P2X receptors are a family of ligand-gated ion channels activated by adenosine trisphosphate (ATP). Preliminary evidence suggests that rat heart contains at least 4 Of the 7 members of the P2X receptor family in addition to a P2X receptor in atrial muscle that has yet to be identified at the molecular level. Very little is known about how these receptors work to regulate transmembrane flux of ions. Structural models of P2X receptors share a common motif. Most of the receptor is made of a large hydrophilic extracellular loop that connects two putative transmembrane domains, TM1 and TM2. TM2 is thought to traverse the membrane as an amphipathic alpha-helix and to form a part of the ion channel. The N- and C- termini are thought to be cytoplasmic. To date, no experimental data supporting this model has been presented. The central hypothesis of the proposal outlined in this application is that a more complete characterization of P2X receptors is needed to understand how ATP and the autonomic nervous system control cardiac output. This project outlines experiments that take the first steps towards accomplishing this goal. We are interested in how these proteins regulate the flow of cations across biological membranes. In this regard, the most fundamental unanswered question is what part of the protein forms the ion channel. We hypothesized that one or both of TM 1 and TM2 participates in forming the water-filled ion channel pore. If so, then the similarities and differences in channel function of receptor subtypes may be explained by the patterns of amino acids in these proteins. Our goal is to identify which amino acids line the pore, and to determine how these residues influence conduction. In addition, we expect that a unique sequence of amino acids explains the unusual profile of the atrial P2X receptor. The cDNA encoding this receptor has yet to be identified, and characterization of the properties of the native receptor of atrial muscle is incomplete. We propose to provide a more complete description of the native receptor that takes into account the new information about P2X receptors that has been learned in the last few years.

心脏功能的微调需要一种控制心脏的方法 比率和收缩的方式。激活 嘌呤能P2X受体可以实现这一目标。 P2X受体 是由腺苷激活的配体门控离子通道的家族 三磷酸盐（ATP）。初步证据表明老鼠心 在P2X受体家族的7个成员中，至少有4个 在心房肌肉中的P2X受体增加尚未 在分子水平上鉴定。关于这些如何了解 受体可调节离子的跨膜通量。结构 P2X受体的模型共有一个共同的基序。大多数受体是 由一个连接两个的大型亲水细胞外环制成 推定的跨膜结构域TM1和TM2。 TM2被认为遍历 膜作为两亲α-螺旋，并形成一部分 离子通道。 N-和C-末端被认为是细胞质。到 日期，尚未介绍任何支持此模型的实验数据。 本应用程序中概述的提案的中心假设是 需要对P2X受体进行更完整的表征 了解ATP和自主神经系统如何控制心脏 输出。该项目概述了采取第一步的实验 实现这一目标。我们对这些如何感兴趣 蛋白质调节阳离子跨生物膜的流动。在 这方面，最根本的未解决问题是 蛋白质形成离子通道。我们假设一个或两个 TM 1和TM2参与形成水填充离子通道孔。 如果是这样，那么 受体亚型可以通过氨基酸的模式来解释 这些蛋白质。我们的目标是确定哪种氨基酸在 孔，并确定这些残基如何影响传导。在 此外，我们预计独特的氨基酸序列可以解释 心房P2X受体的异常曲线。编码这个cDNA 受体尚未确定，并且表征 心房肌肉天然受体的特性不完整。我们 建议提供对本机受体的更完整描述 考虑到有关P2X受体的新信息 在过去的几年中已经学到了。