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BASIS FOR NA MODULATION OF ALPHA2 RECEPTOR FUNCTION

NA 调节 ALPHA2 受体功能的基础

基本信息

批准号：
2838896
负责人：
LEE E LIMBIRD
金额：
$ 30.19万
依托单位：
VANDERBILT UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1979
资助国家：
美国
起止时间：
1979-12-01 至 2000-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/2838896
关键词：
G protein allosteric site alpha adrenergic receptor ion transport laboratory rabbit peptide hormone potassium channel protein isoforms protein structure function protein transport receptor binding receptor coupling sodium tissue /cell culture

项目摘要

DESCRIPTION: The long range goal of studies in the principal investigator's laboratory is to understand, in as precise molecular detail as possible, the mechanism(s) by which alpha2 adrenergic receptors couple to distinct effector systems (such as inhibition of adenylate cyclase, suppression of calcium currents, activation of potassium currents) to elicit their diverse regulatory effects on excitation-secretion coupling. This next phase of the research is based on the discovery that a mutation in a highly conserved residue in the receptor, Asp79Asn, resulted in a loss of allosteric regulation of the receptor to sodium and, more significantly, a selective loss in coupling of the receptor to potassium currents in AtT20 cells. The selective loss of response by the mutated receptors offers an excellent opportunity to explore the roles of hormonal responsive currents in suppression of peptide hormone release in these cells and to gain insight into basic coupling mechanisms of the receptor. Specific aims include: 1) Determination of the relative abilities of wildtype and various mutant receptors to suppress peptide hormone secretion via measurement of ACTH release form AtT20 cells. 2) Evaluation of a series of mutants in the Asp79 position of the alpha2 receptor with regard to allosteric modulation by cations and coupling to inhibition of adenylate cyclase, ion channels, and secretion. 3) Clarification of the molecular basis for perturbation of coupling of the D79N mutation to activation of potassium currents in the AtT20 cells as a means to reveal the G protein involved in coupling this and other similar receptors to potassium currents. 4) Identification of alpha2A-adrenergic receptor associated effector complexes involved in receptor mediated signal transduction by selective immuno-isolation of effector proteins with wildtype versus functionally modified mutant receptors. Overall, the PI believes that these studies will provide new molecular insights regarding alpha2- adrenergic coupling to diverse signal transduction mechanisms as a first step toward developing novel therapeutic agents that are targeted downstream of receptor occupancy, and may provide a degree of specificity for function not attainable by simultaneous modulation of activity at all alpha2 receptors of a given pharmacological type.

描述：校长研究的长期目标研究人员的实验室的目的是了解，以尽可能精确的分子尽可能详细地说明 α2 肾上腺素能发挥作用的机制受体与不同的效应系统耦合（例如抑制腺苷酸环化酶，抑制钙电流，激活钾电流）以引发其不同的调节作用兴奋-分泌耦合。下一阶段的研究基于发现高度保守的残基发生突变受体 Asp79Asn 导致变构调节丧失钠受体，更重要的是，选择性丧失耦合 AtT20 细胞中钾电流受体的变化。选择性损失突变受体的反应提供了一个绝佳的机会探索激素反应电流在抑制中的作用这些细胞中肽激素的释放并深入了解基本受体的偶联机制。具体目标包括：1) 测定野生型和各种突变体的相对能力通过测量 ACTH 抑制肽激素分泌的受体从 AtT20 细胞中释放。 2) 对一系列突变体的评价 α2 受体在变构方面的 Asp79 位置通过阳离子调节并耦合抑制腺苷酸环化酶，离子通道和分泌。 3）分子基础的阐明用于干扰 D79N 突变与激活的耦合 AtT20 细胞中的钾电流作为揭示 G 蛋白的手段参与将该受体和其他类似受体与钾偶联电流。 4) 相关α2A-肾上腺素受体的鉴定效应复合物参与受体介导的信号转导效应蛋白与野生型和野生型的选择性免疫分离功能修饰的突变受体。总体而言，PI 认为这些研究将提供有关 alpha2- 的新分子见解肾上腺素能与多种信号转导机制的耦合作为第一个朝着开发新的靶向治疗药物迈出了一步受体占据的下游，并可能提供一定程度的通过同时调制无法实现的功能特异性给定药理学类型的所有 α2 受体的活性。