糖皮质激素受体。

G G Rousseau, J D Baxter
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引用次数: 6

摘要

糖皮质激素受体存在于大多数哺乳动物组织中,并在许多组织培养系统中得到了详细的研究。对于未暴露于类固醇的细胞,受体存在于可以分离和研究的细胞质部分中。研究糖皮质激素受体的方法依赖于它们与放射性类固醇的高亲和力特异性结合。可逆的相互作用发生在细胞内。它遵循迈克尔动力学,至少在无细胞的细胞质中,并且涉及每个细胞约10,000个位点的热力学均匀种群。受体是一种不对称的微酸性蛋白质,约为10万道尔顿。它非常不稳定,尤其是在未结合的形式下。结合活性取决于巯基的完整性,也可能取决于氨基酸残基的磷酸化。虽然是间接的,但证据压倒性地令人信服,这种蛋白质是生理性糖皮质激素受体。结合和解离的时间动力学与糖皮质激素作用中的事件顺序一致。各种类固醇类似物显示结合特性可预测从他们的糖皮质激素活性。从某些培养的细胞系中失去结合蛋白伴随着对糖皮质激素的无反应。受体在组织中的广泛分布与糖皮质激素在调节中的广泛作用相似。最后,受体的核结合与类固醇的核效应之间存在很强的相关性。糖皮质激素受体可以与其他糖皮质激素结合蛋白区分,基于它们的类固醇特异性和物理化学性质。没有明确的证据表明受体在不同的组织中是不同的,事实上,它在不同的物种中是非常相似的。与其他系统不同,受体浓度似乎不受其配体或其他激素的调节。然而,某些对糖皮质激素过敏和过敏的病例似乎是由受体水平的变化引起的。数据表明,受体可以以非活性和活性形式存在。前者在没有类固醇或有类固醇的情况下占优势。糖皮质激素激动剂结合活性形式,使其被“激活”并随后与细胞核结合。分离细胞质中的所有受体似乎都不能立即被激动剂占据,这可能是由于受体从无活性形式转化为活性形式所需的时间。受体结合与糖皮质激素反应之间的相关性表明,受体是反应幅度和动力学的限速因素,这一发现对机制具有重要意义。
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Glucocorticoid receptors.

Glucocorticoid receptors are found in most mammalian tissues and have been studied in detail in a number of tissue culture systems. With cells that have not been exposed to steroids, the receptors are found in the cytoplasmic fraction from which they can be isolated and studied. Methods for studying glucocorticoid receptors depend on their high-affinity specific binding of radioactive steroids. The reversible interaction is intracellular. It follows Michaelian kinetics, at least in cell-free cytosol, and involves a thermodynamically homogeneous population of about 10 000 sites per cell. The receptor is an asymmetric, slightly acidic protein of about 100 000 daltons. It is very labile, especially in the unbound form. Binding activity depends on the integrity of thiol groups and perhaps on phosphorylation of amino acid residues. Although indirect, the evidence is overwhelmingly convincing that this protein is the physiologic glucocorticoid receptor. The time-kinetics of binding and dissociation are consistent with the sequence of events in glucocorticoid action. Various steroid analogs display binding characteristics predictable from their glucocorticoid activity. Loss of the binding protein from certain cultured cell lines is accompanied by unresponsiveness to glucocorticoids. The extensive tissue distribution of receptors parallels the extensive role of glucocorticoids in regulation. Finally, there is a strong correlation between nuclear binding of receptors and nuclear effects of the steroid. The glucocorticoid receptor can be distinguished from other glucocorticoid-binding proteins, based on their steroid specificity and physicochemical properties. There is no clear-cut demonstration that the receptor differs from tissue to tissue, and it is in fact very similar in various species. Unlike in other systems, receptor concentration does not seem to be regulated by its ligand or by other hormones. However, certain cases of hypo- as well as hypersensitivity to glucocorticoids appear to result from changes at the receptor level. The data indicate that the receptor can exist in inactive and active forms. The former predominate in the absence of steroid or when an angatonist is bound. Glucocorticoid agonists bind the active form, allowing it to be "activated" and subsequently bound to the nucleus. All of the receptors in isolated cytosol do not appear to be available for immediate occupancy by an agonist and this may be due to the time required for conversion of the receptors from inactive to active forms. The correlations between receptor binding and the glucocorticoid response indicate that the receptor is a rate-limiting factor in the magnitude and kinetics of the response, and this finding has important implications regarding mechanisms.

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