PHARMACOLOGY OF CARDIOEXCITATORY NEUROPEPTIDES

心脏兴奋性神经肽的药理学

• 批准号: 3339799
• 负责人: MICHAEL J GREENBERG
• 金额: $ 13.52万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 1981
• 资助国家: 美国
• 起止时间: 1981-06-01 至 1986-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3339799
• 关键词: amides; cardiotonic agents; cyclic AMP; cyclic GMP; ganglions; heart pharmacology; ion transport; peptides

FMRFamide (Phe-Met-Arg-Phe-NH2) is a neuropeptide isolated from clam ganglia; it is stored in granules, and released upon depolarization. FMRFamide is a potent molluscan pharmacon: it is cardioexcitatory or inhibitory depending on species; it causes contractures of various muscles and affects neuronal activity. FMRFamide is only one example of a set of heterogenous, but structurally and functionally homologous, molluscan neuropeptides. Moreover, it is hypothesized that FMRFamide-like peptides are widely distributed among animals, including vertebrates, and may have had a common origin with the opioid peptides in protein evolution. This project focuses on the phyletic distribution and mechanisms of action of FMRFamide. First, three peptides, already identified in the brains of the gastropods, Busycon contrarium and Helix aspersa, will be further purified by high performance liquid chromatography, and their amino acid compositions and sequences determined. The extraction and purification steps will be monitored by bioassays specific for FMRFamide (Busycon radula protactor muscle) or of the opioid peptides (guinea-pig ileum and mouse vas deferens). FMRFamide-like peptides will also be sought in other tissues: porcine adrenal medulla and sympathetic ganglia; and the central ganglia from other invertebrate phyla. As these peptides are characterized, their subcellular localization will be determined, and their release by potassium depolarization will be demonstrated. A particle-bound peptidase, coverting N-terminal extended precursors to FMRFamide, has been proposed; an attempt will be made to demonstrate it. FMRFamide receptors will be characterized by structure-activity studies on particular molluscan hearts and muscles and on rabbit vascular smooth muscle; the selected preparations are sensitive to the peptide; and their responses exemplify the range of its effects. The inotropic effects of FMRFamide will be correlated with its actions on cyclic nucleotide levels. The sucrose gap technique will be used to correlate electrical and mechanical responses.

FMRFamide (Phe-Met-Arg-Phe-NH2) 是一种从蛤中分离出来的神经肽 神经节;它储存在颗粒中，并在去极化时释放。 FMRFamide 是一种有效的软体动物药物：它具有心脏兴奋或 抑制作用取决于物种；它会导致各种肌肉挛缩 并影响神经元活动。 FMRFamide 只是一组的一个例子 异质但结构和功能同源的软体动物 神经肽。 此外，据推测 FMRFamide 样肽 广泛分布于包括脊椎动物在内的动物中，并且可能具有 在蛋白质进化中与阿片肽有共同的起源。 这 项目重点研究物种分布和作用机制 FMRF酰胺。 首先，已经在人的大脑中鉴定出三种肽 腹足类动物 Busycon contrarium 和 Helix aspersa 将被进一步纯化 高效液相色谱法测定其氨基酸 确定的组成和序列。 提取和纯化 步骤将通过 FMRFamide 特异性生物测定（Busycon radula 前肌）或阿片肽（豚鼠回肠和小鼠血管 输精管）。 FMRFamide 样肽也将在其他组织中寻找： 猪肾上腺髓质和交感神经节；和中央神经节 来自其他无脊椎动物门。 由于这些肽的特征，它们 将确定亚细胞定位，并通过钾释放它们 将表现出去极化作用。 颗粒结合肽酶，隐蔽 已提出 FMRFamide 的 N 末端延伸前体；一次尝试 将进行演示。 FMRFamide 受体将被表征 通过对特定软体动物心脏和肌肉的结构-活性研究 以及对兔血管平滑肌的影响；选定的制剂是 对肽敏感；他们的回应体现了其范围 影响。 FMRFamide 的正性肌力作用将与其相关 对环核苷酸水平的作用。 蔗糖间隙技术将是 用于关联电气和机械响应。