URINARY BLADDER MUSCARINIC RECEPTOR SUBTYPES

膀胱毒蕈碱受体亚型

• 批准号: 2142923
• 负责人: Michael Raymond Ruggieri
• 金额: $ 18.42万
• 依托单位: TEMPLE UNIV OF THE COMMONWEALTH
• 依托单位国家: 美国
• 财政年份: 1991
• 资助国家: 美国
• 起止时间: 1991-08-01 至 1999-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2142923
• 关键词: G protein; SDS polyacrylamide gel electrophoresis; electron microscopy; fluphenazine; high performance liquid chromatography; human tissue; immunocytochemistry; immunoprecipitation; laboratory rabbit; laboratory rat; messenger RNA; muscarinic receptor; muscle cells; neuropharmacology; neurophysiology; pertussis toxin; phosphorylation; protein kinase; receptor coupling; receptor expression; receptor sensitivity; tissue /cell culture; urinary bladder; urinary tract motility /pressure; western blottings

In clinical Urology, muscarinic drug therapy with both agonists (bethanechol) and antagonists (oxybutynin) is used to a considerable extent. However, the function of the muscarinic receptors in the bladder have not been unequivocally determined at the subtype level. This is an important distinction since it appears that the cellular response to neuronally released acetylcholine can be either excitatory or inhibitory, perhaps depending on the muscarinic receptor subtype stimulated. On the basis of the action of antagonists 3 muscarinic receptor subtypes (designated by upper case "M", M1 - M3) can be defined although none of the antagonists yet studied is highly selective for one receptor subtype over all of the others. Therefore previous pharmacological characterization of muscarinic receptor subtypes represents the composite properties of a heterogenous mixture of receptor subtypes. Two recent, interrelated advances have made it possible to determine the density, cellular location and physiological regulation of muscarinic receptor subtypes: the cloning of genes for muscarinic receptor subtypes and development of subtype specific antibodies. The molecular biology approach has resulted in the cloning of a family of muscarinic genes which share the same proposed overall structure and a large degree of protein sequence homology. Five muscarinic receptors (designated by lower case "m", m1-m5) are known and there are indications that more may exist. Our previous studies have determined that two subtypes of muscarinic receptor (m2 and m3) are present in bladder tissue from rat, rabbit, guinea pig, and human, suggesting that one or both may be involved in bladder contractility. These receptors mediate their effects through different biochemical mechanisms, and presumably the regulation of receptor levels and activity are independent since our previous studies have shown differential regulation of the two subtypes under various experimental conditions. We will attempt to identify which subtype of receptor regulates bladder contractility, and more closely examine the biochemical events associated with receptor activation. These studies should elucidate potential mechanisms by which bladder muscarinic receptor levels and activity are regulated, and determine which mechanisms allow selective regulation of individual receptor subtypes. The long range goal of this project is to define the role of the different muscarinic receptor subtypes in bladder function.

在临床泌尿科中，两种激动剂的毒蕈碱药物治疗 （贝塞纳啤酒）和拮抗剂（oxybutynin）用于相当大的 程度。 但是，膀胱中毒蕈碱受体的功能 在亚型水平上尚未明确确定。 这是一个 重要的区别，因为看来细胞对 神经释放的乙酰胆碱可以是兴奋性的，也可以是抑制性的 也许取决于被刺激的毒蕈碱受体亚型。 在 拮抗剂3毒蕈碱受体亚型的作用的基础 （由上案例“ M”，M1 -M3指定），尽管没有 尚未研究的拮抗剂对于一种受体亚型具有很高的选择性 在其他所有人中。 因此先前的药理 毒蕈碱受体亚型的表征代表复合材料 受体亚型异源混合物的特性。 最近两个 相互关联的进步使确定密度， 毒蕈碱受体的细胞位置和生理调节 亚型：毒蕈碱受体亚型基因的克隆和 亚型特异性抗体的开发。 分子生物学 方法导致了毒蕈碱基因家族的克隆，该基因家族 共享相同建议的总体结构和大量蛋白质 序列同源性。 五个毒蕈碱受体（由较低病例指定 “ M”，M1-M5）是已知的，并且有迹象表明可能存在更多。 我们的 先前的研究确定了两种亚型的毒蕈碱受体亚型 （M2和M3）存在于大鼠，兔子，豚鼠，膀胱组织中 和人类，暗示一个或两个都可能参与膀胱 收缩力。 这些受体通过不同的 生化机制，大概是受体水平的调节 由于我们以前的研究表明，活动是独立的 在各种实验下对两个亚型的差分调节 状况。 我们将尝试确定哪个受体亚型 调节膀胱收缩性，并更仔细地检查生化 与受体激活相关的事件。 这些研究应该 阐明膀胱毒蕈碱受体水平的潜在机制 调节活动，并确定哪些机制允许选择性 调节单个受体亚型。 远距离目标 项目是定义不同毒蕈碱受体的作用 膀胱功能中的亚型。