GONADOTROPIN ACTIONS IN LEYDIG TUMOR CELLS

从机制上讲，LH/CG的作用可以在以下水平进行调节： LH/CG受体（LHR）通过减少受体数量（减少- 调节）或通过恒定数量的 受体从其效应器系统（解偶联）。 我们先前已经 表明hCG诱导的LHR下调主要是由于 增加的受体降解， 结合的荷尔蒙 我们还发现LHR的磷酸化 对于hCG诱导的解偶联是必要的，但不是充分的。 本文提出的研究旨在进一步了解 解偶联和下调LHR的分子基础。的 具体目标如下：（1）鉴定 磷酸化LHR和变得磷酸化的残基;（2） 检查LHR棕榈酰化对hCG诱导的 解偶联;（3）确定LHR激活在LHR中的重要性- 介导的内吞作用;和（4）检查的分子基础， 在Leydig肿瘤细胞中检测到的LHR下调增加， 与表达重组LHR的非靶细胞相比。 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方法， 关于在其水平上调节激素作用的信息 受体认为，这种水平的调节同样有效， 重要. 一种高效且高度特异性的方法， 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 因此，研究应提供有关监管的宝贵见解， LHR、糖蛋白激素受体和G 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.