ANGIOTENSIN RECEPTOR SUBTYPES

血管紧张素Ⅱ(AngII)是肾素的主要效应分子 血管紧张素系统与血压和液体的主要决定因素 音量。分子性质研究的新进展 血管紧张素转换酶受体(AT受体)落后于其他受体 肾素-血管紧张素系统的组成部分。尽管AT的证据 受体的异质性已经积累了二十多年，朝着 由于缺乏信息，AT受体家族的定义一直受到阻碍 受体一级结构。在新开发的非肽类药物基础上 配体，存在两类AT受体，称为AT1和AT2， 已经被提出了。然而，目前还没有已知的生物学反应。 与AT2结合位点相关联。因此，它的存在不可能是 早些时候的研究预测。因此，AT1受体内的多样性 类很可能是AT受体异质性的早期证据。 编码大鼠血管平滑肌AT1受体的cDNA现在已经被 与世隔绝。该克隆编码的氨基酸序列共有7个 疏水性的膜跨越结构和保守的氨基酸 具有视紫红质样的G蛋白偶联受体超家族的基序。 基因组Southern分析显示，有几条杂交条带与 克隆的cDNAs探针提示可能存在分子多样性。 AT1受体。这项建议的目标是严格界定 通过分离编码cDNA和/或基因的这种多样性的分子基础 其他AT1受体亚型。使用一个模型系统，其中每个克隆 受体是在细胞系中唯一地转染和表达的，它们的 药理属性和生化信号机制将是 在缺乏AT受体异质性的情况下进行研究 组织模型。建议进行实验，以定位组织和 原位杂交法检测AT1受体亚型的细胞分布 和免疫细胞化学方法。这些研究应该提高人们的知识水平 AT受体亚型的药理、功能和分布的研究。 应促进选择性治疗的合理发展 治疗心血管疾病的药物，并提供见解 AT受体潜在的病理生理作用。

Angiotensin II (angII) is the major effector molecule of the renin angiotensin system and a principal determinant of blood pressure and fluid volume. Progress towards an understanding of the molecular properties of receptors for angII (AT receptors) has lagged that achieved for other components of the renin-angiotensin system. Although evidence of AT receptor heterogeneity has accumulated over two decades, progress towards defining an AT receptor family has been hindered by a lack of information on receptor primary structure. On the basis of newly developed nonpeptidic ligands, the existence of two classes of AT receptors, termed AT1 and AT2, has been proposed. However, no known biological response has been associated with AT2 binding sites. Thus, its existence could not have been predicted by earlier studies. Therefore, diversity within the AT1 receptor class most likely accounts for early evidence of AT receptor heterogeneity. A cDNA encoding a rat vascular smooth muscle AT1 receptor has now been isolated. the amino acid sequence encoded by this clone shares seven hydrophobic, putative membrane spanning structures and conserved amino acid motifs with the rhodopsin-like superfamily of G-protein-coupled receptors. Genomic Southern analysis demonstrates several hybridizing bands to a cloned cDNA probe that suggests the possibility of molecular diversity in AT1 receptors. The objective of this proposal is to define rigorously the molecular basis for this diversity by isolating cDNAs and/or genes encoding additional AT1 receptor subtypes. Using a model system whereby each cloned receptor is uniquely transfected and expressed in a cell line, their pharmacological attributes and biochemical signalling mechanisms will be studied in the absence of AT receptor heterogeneity commonly found in other tissue models. Experiments are proposed to localize the tissue and cellular distribution of AT1 receptor subtypes using in situ hybridization and immuno-cytochemical approaches. These studies should improve knowledge of the pharmacology, function and distribution of AT receptors subtypes. They should improve the rational development of selective therapeutic agents for the treatment of cardiovascular disorders, and provide insights into potential pathophysiological roles of AT receptors.