MOLECULAR CHARACTERIZATION OF ANGIOTENSIN II RECEPTORS

血管紧张素II是一种八肽，来源于血管紧张素原 系统，该系统引起与监管有关的广泛影响， 血压以及盐和水的代谢。 的确， 用于人类高血压的有效治疗剂通过阻断 血管紧张素II的形成。 《行动纲领》的广泛和长期目标 拟议的研究是血管紧张素II的分子特征 受体。 本申请的具体目标是研究 血管紧张素II，1型受体分子的明显新形式 从大鼠脑垂体前叶克隆而来。 这个克隆体不同于 血管紧张素II，1型受体最近被描述用于血管 平滑肌和肾脏。 脑垂体形式的受体具有 与血管/肾脏在核苷酸水平上的总体同一性为74% 然而，它编码具有95%氨基酸同一性的蛋白质。 两种形式的受体的差异并不符合 选择性RNA剪接表明垂体和血管/肾脏 受体由不同的基因编码。 配体结合 这两种形式的受体的特征是相似的。 它们的组织 mRNA表达略有不同，垂体和血管 平滑肌显示其同源受体的最高水平。 最后，垂体mRNA水平受到雌激素的强烈调节。 该提案的具体目的是：1）比较配体结合 两种形式的受体的特征; 2）识别第二种 受体的垂体形式所利用的信使系统; 3） 确定编码这两种基因的mRNA的差异组织分布， 4）检测雌激素对mRNA表达的影响 不同组织中两种形式的受体; 5）克隆，测序， 表征编码垂体形式受体的基因; 6） 分离、排序和描述人类形态的垂体 受体; 7）确定两种形式受体的细胞定位 mRNA使用原位杂交，和; 8）产生单克隆抗体 从这两种形式的受体衍生的肽。 这些研究 应该提供有关人类病因和治疗的新信息 高血压

Angiotensin II is an octapeptide derived from the renin-angiotinsenogen system which evokes a broad spectrum of effects related to regulation of blood pressure and to salt and water metabolism. Indeed, the most effective therapeutic agent for human hypertension acts by blocking the formation of angiotensin II. The broad, long-term objective of the proposed studies is the molecular characterization of angiotensin II receptors. The specific objective of this application is the study of an apparently new form of the angiotensin II, type 1 receptor molecularly cloned from the rat anterior pituitary gland. This clone differs from the angiotensin II, type 1 receptor recently described for vascular smooth muscle and kidney. The pituitary form of the receptor has an overall 74% identity at the nucleotide level with the vascular/kidney receptor; however, it encodes a protein with a 95% amino acid identity. The differences in the two forms of receptors are not consistent with alternative RNA splicing suggesting that the pituitary and vascular/renal receptors are encoded by separate genes. The ligand binding characteristics of the two forms of receptors are similar. Their tissue mRNA expression differs somewhat in that the pituitary and vascular smooth muscle show the highest levels of their cognate receptors. Finally, pituitary levels of mRNA are strongly regulated by estrogens. The Specific Aims of the proposal are to: 1) compare the ligand-binding characteristics of the two forms of receptors; 2) identify the second messenger system utilized by the pituitary form of the receptor; 3) determine the differential tissue distribution of mRNAs encoding the two forms of receptors; 4) test the effects of estrogens on mRNA expression of the two forms of receptors in various tissues; 5) clone, sequence, and characterize the gene encoding the pituitary form of the receptor; 6) isolate, sequence, and characterize the human form of the pituitary receptor; 7) determine the cell localization of the two forms of receptor mRNA using in situ hybridization, and; 8) produce monoclonal antibodies to peptides derived from the two forms of receptors. These studies should provide new information about the etiology and treatment of human hypertension.