MECHANISM OF ACTION OF PEPTIDE HORMONES IN STEROIDOGENIC CELLS

肽激素在类固醇细胞中的作用机制

• 批准号: 3942019
• 负责人: M L DUFAU
• 金额: --
• 依托单位: EUNICE KENNEDY SHRIVER NATIONAL INSTITUTE OF CHILD HEALTH & HUMAN DEVELOPMENT
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/3942019
• 关键词: Leydig cells; adenylate cyclase; androgens; angiotensin II; autoradiography; chorionic gonadotropin; cyclic AMP; density gradient ultracentrifugation; electron microscopy; embryo /fetus cell /tissue; estradiol; gonadotropin releasing factor; hormone regulation /control mechanism; luteinizing hormone; peptide hormone; radioimmunoassay; radiotracer; steroid biosynthesis; steroid hormone biosynthesis; testis; testosterone; tissue /cell culture

Stimulation of the andorgen pathway occurs mainly through cAMP mediated mechanism. The stimulatory event can be negatively influenced by the action of certain hormones. In recent studies we have demonstrated the presence functional angiotensin II (AII) receptors in the Leydig cell of high affinity Ka 1.7 nM and low capacity 2,000 sites per cell. AII inhibits GTP and LH sitmulated adenylate cyclase in Leydig cell membranes. This hormone also acutely inhibits LH stimulation of cyclic AMP pools and testosterone production in Leydig cells. These effects were prevented by incubation with pertussis toxin and reversed by 8- bromo cAMP additions indicating that AII actio in the Leydig cell occurs through the guanyl nucleotide inhibitory unit of adenylate cyclase (Gi), findings that have further emphasized the importance of the cAMP pathway in the Leydig cell. In addition to the potentiation and direct stimulatory effect of forskolin, a dose-dependent inhibitory effect of forskolin (ID50, pM) on basal and hCG-stimulated cyclic AMP pools and testosterone production were demonstrated through inhibition of adenylate cyclase via direct or indirect activation of Gi. High affinity action of forkolin is of value for direct evaluation of functional Gi activity. Unlike the adult Leydig cell, the fetal and immature cell are refractory to desensitization and maintain up-regulated LH receptor and steroidogenic functions, and their inability to be desensitized by gonadotropin is attributed to the absence of an estrogen-mediated regulation of the androgen pathway. The fetal testis possess in addition to the predominant fetal cell population a small population of transitional cells with functional capacities of the adult cell. After appropriate treatment of fetal cultures (i.e. estrogen, and frequent or a high gonadotropin dose) emerge a functional adult-like cell type from the fetal Leydig cell population. The cultured fetal Leydig cell system provides a useful model to elucidate LH, GnRH action, beta-endorphin regulation and the mechanism involved in the development of gonadotropin-induced estradiol-mediated desensitization of steroidogenesis.

雄激素途径的刺激主要通过cAMP发生 中介机制。 刺激事件可以是负面的， 受某些激素作用的影响。 在最近的研究中 我们已经证明了功能性血管紧张素II（AII）的存在， Leydig细胞中的高亲和力Ka 1.7 nM和低亲和力Ka 1.7 nM受体， 每个小区可容纳2,000个站点。 AII抑制刺激的GTP和LH 间质细胞膜中的腺苷酸环化酶。 这种激素也 急性抑制环AMP池的LH刺激， 睾丸激素的产生。 这些效应 用百日咳毒素孵育预防，用8- 溴环腺苷酸增加表明，在Leydig细胞中的AII作用 通过腺苷酸的鸟苷酸抑制单位发生 环化酶（Gi），研究结果进一步强调了 cAMP途径在Leydig细胞中的重要性。 此外 增强和直接刺激作用的毛喉素， 毛喉素（ID 50，pM）对基底细胞的剂量依赖性抑制作用 和hCG刺激的环AMP池和睾酮产生 通过抑制腺苷酸环化酶， 直接或间接激活Gi。 高亲和力作用 forkolin具有直接评价功能性Gi活性的价值。 与成年间质细胞不同，胎儿和未成熟的细胞 不敏感并维持LH上调 受体和类固醇生成功能，以及它们不能被 促性腺激素脱敏是由于缺乏一个 雌激素介导的雄激素途径调节。 胎儿 睾丸除了拥有主要的胎儿细胞群外， 一小群具有功能的过渡细胞 成人细胞。 对胎仔培养物进行适当处理后 (i.e.雌激素和频繁或高剂量的促性腺激素）出现 来自胎儿Leydig细胞的功能性成人样细胞类型 人口 培养的胎儿Leydig细胞系统提供了一种 阐明LH、GnRH作用、β-内啡肽的有用模型 发展中的监管和机制 促性腺激素诱导的雌二醇介导的 类固醇生成