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控制心脏的方法 心率和收缩力的变化。激活 嘌呤能P2 X受体可能实现这一目的。p2 x受体 是腺苷激活的配体门控离子通道家族 三磷酸（ATP）。初步证据显示老鼠的心脏 含有P2 X受体家族7个成员中的至少4个， 除了心房肌中的P2 X受体， 在分子水平上识别。我们对它们是如何产生的知之甚少 受体的作用是调节离子的跨膜通量。结构 P2 X受体的模型共享共同的基序。大多数受体是 由一个大的亲水性细胞外环组成， 推测的跨膜结构域，TM 1和TM 2。TM 2被认为是穿越 膜作为两亲性α-螺旋，并形成膜的一部分。 离子通道N-和C-末端被认为是细胞质的。到 迄今为止，尚未提供支持该模型的实验数据。 本申请中概述的建议的中心假设是 需要对P2 X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 为了实现这一目标。我们感兴趣的是这些 蛋白质调节阳离子穿过生物膜的流动。在 在这方面，最根本的未解问题是， 蛋白质形成离子通道。我们假设 TM 1和TM 2参与形成水填充的离子通道孔。 如果是这样的话，那么在渠道功能的异同， 受体亚型可以用氨基酸的模式来解释， 这些蛋白质。我们的目标是确定哪些氨基酸符合 孔，并确定这些残留物如何影响传导。在 此外，我们预计，一个独特的氨基酸序列解释了 心房P2 X受体的异常分布。编码这个的cDNA 受体尚未被鉴定， 心房肌的天然受体的性质是不完整的。我们 我建议提供一个更完整的描述天然受体 它考虑了P2 X受体的新信息， 在过去的几年里已经学会了。