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: 4693722
• 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/4693722
• 关键词: Leydig cells; androgens; autoradiography; cholesterol; chorionic gonadotropin; cyclic AMP; density gradient ultracentrifugation; electron microscopy; embryo /fetus cell /tissue; estradiol; gonadotropin releasing factor; hormone regulation /control mechanism; luteinizing hormone; microsomes; mitochondria; peptide hormone; pituitary adrenal axis; pituitary gonadal axis; radioimmunoassay; radiotracer; steroid biosynthesis; steroid hormone biosynthesis; sterol esterase; testis; testosterone; tissue /cell culture

The control of androgen production by the Leydig cell is directly regulated by luteinizing hormone via specific receptors. Treatment with gonadotropin causes initial LH receptor up-regulation, and desensitization of steroidogenic enzymes: "early lesion" (prior to prengenolone) and "late lesion" E2-dependent (17 Alpha-hydroxylase 17-20 desmolase). These are independent of receptor loss or protein kinase activation. The negative control of receptors and lesions is not observed in the immature or fetal Leydig cell. The goal of this project is to understand the steps involved in the hormonal control of testicular function. We have demonstrated that as a result of gonadotropin action, E2-mediated desensitization is initiated by a cyclic AMP-dependent early activation of aromatase, which is followed by a significant rise in E2 formation due to an increased substrate availability. Leydig cells are the major site of E2 synthesis in theadult rat testis. The low aromatase activity observed in immature rat Leydig cells could explain the lack of desensitization observed in fetal and early life. E2 action that precedes desensitization includes increased synthesis of a 27K E2-regulated protein. This protein was found to be immunologically similar to a major E2-regulated 27K protein of MCF-7 cells. This provides a sensitive probe for detection of E2 action and should prove useful for further functional and structural characterization of the protein and for studies of the nuclear actions of E2 in the Leydig cell. There is a continous basal supply of steroidogenic cholesterol in the mitochondrion regardless of the presence of gonadotropins, a process probably regulated by the levels of endogenous steroids. The early lesion is not due to an inappropriate concentration of precursors, since the levels of cholesterol in the inner mitchondrial membrane are increased. A heat-labile inhibiting protein factor was identified in mitochondria and shown to be markedly increased by hCG treatment. This factor, which competitively inhibits cholesterol side-chain cleavage activity, could contribute to the early steroidogenic lesion and may also serve as an endogenous modulator of steroid hormone biosynthesis.

睾丸间质细胞直接调控雄激素的产生