Hormone-stimulated metabolism of inositol lipids and its relationship to hepatic receptor function.
Hormone-stimulated metabolism of inositol lipids and its relationship to hepatic receptor function.
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激素刺激的肌醇脂质代谢及其与肝受体功能的关系。
DOI：
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发表时间：
1981
影响因子：
3.9
通讯作者：
R. Michell
中科院分区：
文献类型：
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作者：
C. Kirk;J. Creba;C. Downes;R. Michell
磷脂肌醇分解和Ca2+动员受体激素和神经递质通过改变胞质Ca2+离子浓度发挥生理作用的一个普遍特征是它们能够影响PtdIns的代谢*（参见michel & Kirk， 1981，参考文献）。这一组的激素和神经递质增强了pttin在靶细胞中的结合[32PIP]，无论在哪里进行适当的实验，这种增强的pttin标记已被证明是激素刺激的pttin降解的继发因素（michel & Kirk, 1981）。与此类配体的其他生理效应不同，增强的PtdIns对Ca2+耗尽相对不敏感，并且不会被离子载体A23诱发187。这些观察结果表明，PtdIns的降解是受体激活的直接结果，受体激活先于并可能引起细胞质中Ca2+的动员（michel, 1975）。我们试图在大鼠肝细胞中验证这一假设，其中至少有三种Ca*+动员激素（血管加压素、血管紧张素和肾上腺素通过a受体起作用）引起PtdIns的分解，而这种分解似乎不是由细胞内Ca2+浓度的升高介导的（Kirk等，1977,1978）。1979,1980, 1981；比拉和米歇尔，1979；michel et al., 1979; Tolbert et al., 1980)。抗利尿激素刺激PtdIns分解的浓度依赖性与3h - lys]抗利尿激素与肝细胞受体的结合曲线非常相似（图1），进一步表明PtdIns分解可能参与肝利尿激素受体的刺激-反应耦合机制。相比之下，描述肝细胞Ca2+动员和糖原磷酸化酶激活的浓度依赖性的曲线分别向左偏移了约一个和两个数量级（图1）。我们解释这些结果表明，只有一小部分肝脏抗利尿激素受体需要占用，以激发最大的磷酸化酶激活，而最大的Ca2+释放需要更大（但次最大）的受体占用。因此，对于这两种作用存在“受体储备”，但只有当所有的抗利尿激素受体都被占据时，pttin的最大降解才会被激发（Kirk等人，1981）。因此，肝细胞中抗利尿激素刺激的PtdIns降解似乎不是细胞内Ca2+动员的结果，而是与受体占据密切相关。因此，它满足了肝抗利尿激素受体刺激-反应耦合反应的基本标准，但我们在无细胞系统中证明这一现象的尝试迄今为止失败了。此外，当肝细胞被抗利尿激素刺激5min，然后进行亚细胞分离时，PtdIns的消耗并不局限于质膜（激素受体的位置），而是在各种胞内细胞器的膜中富集的组分中观察到（Kirk等，1998）。
Phosphatidvlinositol breakdown and Ca2+ -mobilizing receptors A universal feature of hormones and neurotransmitters that exert their physiological effects through changes in cytosolic Ca2+ ion concentration is their ability to influence the metabolism of PtdIns* (see Michell & Kirk, 1981, for references). Hormones and neurotransmitters of this group enhance the incorporation [32PIP, into PtdIns in their target cells and, wherever the appropriate experiments have been performed, this enhanced PtdIns labelling has been shown to be secondary to hormone-stimulated PtdIns degradation (Michell & Kirk, 198 1). Unlike the other physiological effects of such ligands, enhanced PtdIns breakdown in relatively insensitive to Ca2+ depletion and it is not evoked by the ionophore A23 187. These observations lead to the suggestion that the degradation of PtdIns is a direct consequence of receptor activation, which precedes, and may evoke, Ca2+-mobilization in the cytosol (Michell, 1975). We have sought to test this hypothesis in rat hepatocytes, where at least three Ca*+-mobilizing hormones (vasopressin, angiotensin and adrenaline acting through a, receptors) cause a breakdown of PtdIns that does not appear to be mediated by a rise in intracellular Ca2+ concentration (Kirk et al., 1977, 1978. 1979, 1980, 1981; Billah & Michell, 1979; Michell et al., 1979: Tolbert et al., 1980). A further indication that PtdIns breakdown may be involved in the mechanism of stimulus-response coupling at hepatic vasopressin receptors was provided by the observation that the concentration dependence of vasopressinstimulated PtdIns breakdown is very similar to the binding curve for 3H-Lyss]vasopressin at hepatocyte receptors (Fig. I) . In contrast, the curves describing the concentration dependence of hepatocyte Ca2+-mobilization and glycogen phosphorylase activation are displaced by about one and two orders of magnitude respectively to the left (Fig. I). We interpret these results to indicate that only a small proportion of the hepatic vasopressin receptors need be occupied to provoke maximum phosphorylase activation, whereas maximum Ca2+ release requires greater (but submaximal) receptor occupation. Thus there is a 'receptor reserve' for these two effects, but maximum PtdIns degradation is only provoked when all the vasopressin receptors are occupied (Kirk et al., 1981). It therefore seems that vasopressin-stimulated PtdIns degradation in hepatocytes is not a consequence of intracellular Ca2+-mobilization and it appears instead to be intimately coupled to receptor occupation. It thus fulfills the basic criteria expected of a reaction involved in stimulus-response coupling at hepatic vasopressin receptors, but our attempts to demonstrate the phenomenon in cell-free systems have so far failed. Furthermore, when hepatocytes are stimulated with vasopressin for 5min and then subjected to subcellular fractionation, PtdIns depletion is not confined to the plasma membrane (the site of hormone receptors), but is observed in fractions enriched in membranes from a variety of intracellular organelles (Kirk et al., I98 1).