GONADOTROPIN ACTIONS IN LEYDIG TUMOR CELLS

从机制上讲，黄体生成素/卵泡刺激素的作用可以在 促黄体生成素/促性腺激素受体(LHR)通过减少受体的数量(下调- 规则)或通过恒定数量的 受体从其效应器系统中分离(解偶联)。我们之前已经 表明hCG对LHR的下调主要是由于 随之而来的受体降解增加的内吞作用 结合的荷尔蒙。我们还证明了LHR的磷酸化 对于hCG诱导的解偶联是必要的，但不是充分的。 本文建议的研究旨在加深我们对 LHR解偶联和下调的分子基础。这个 具体目标如下：(1)确定 使LHR和磷酸化的残基磷酸化；(2) LHR棕榈酰化在hCG诱导中的作用 解偶联；(3)确定LHR激活在LHR- 介导的内吞作用；以及(4)检查 在间质肿瘤细胞中检测到的LHR下调增加 与表达重组LHR的非靶细胞进行比较。 虽然很明显，循环激素水平的变化是 调节靶细胞反应性的有效手段正在出现 关于荷尔蒙活动在其水平上的调节的信息 接受者辩称，这种水平的监管同样有效， 很重要。一种高效且高度特定的目标细胞方式 调节他们对持续刺激的反应是通过改变 激素受体的功能特性或数量。我们的 因此，研究应该为监管提供有价值的见解 LHR、糖蛋白激素受体和G细胞的功能 通常是蛋白质偶联受体。

Mechanistically, the actions of LH/CG can be regulated at the level of the LH/CG receptor (LHR) by reducing the number of receptors (down- regulation) or by the functional uncoupling of a constant number of receptors from its effector system (uncoupling). We have previously shown that the hCG-induced down-regulation of the LHR is mostly due to the increased receptor degradation that ensues following endocytosis of the bound hormone. We have also shown that phosphorylation of the LHR is necessary but not sufficient for the hCG-induced uncoupling. The studies proposed herein seek to further our understanding of the molecular basis of uncoupling and down-regulation of the LHR. The specific aims are as follows: (1) identify the kinases that phosphorylate the LHR and the residues that become phosphorylated; (2) examine the involvement of palmitoylation of the LHR on hCG-induced uncoupling; (3) determine the importance of LHR activation in LHR- mediated endocytosis; and (4) examine the molecular basis for the increased down-regulation of the LHR detected in Leydig tumor cells when compared to non-target cells expressing the recombinant LHR. While it is clear that changes in the levels of circulating hormones are effective means of modulating target cell responsiveness, emerging information about the regulation of hormone action at the level of their receptors argues that this level of regulation is equally effective and important. An efficient and highly specific way by which target cells regulate their responsiveness to continuous stimulation is by changing the functional properties or the numbers of hormone receptors. Our studies should thus provide valuable insights about the regulation of the function of the LHR, the glycoprotein hormone receptors and the G protein-coupled receptors in general.