Steroid-receptor complex

Corticosteroids a chronic painless myopathy associated with the long-term use of corticosteroids is a particularly common example of drug-induced muscle disorder. It is almost certain that mild cases are overlooked because steroids are so frequently used to treat inflammatory myopathies such as polymyositis. Fluorinated steroids are particularly frequently implicated, and the incidence of drug-induced muscle disease is dose and time-related. The presence of muscle weakness can even complicate topical steroid therapy. Corticosteroid-induced myopathy is mediated via intramuscular cytosolic steroid receptors. The steroid-receptor complexes inhibit protein synthesis and interfere with oxidative phosphorylation. The myopathy is associated with vacuolar changes in muscle, and the accumulation of cytoplasmic glycogen and mitochondrial aggregations. 

The cellular mechanism of action of hydrocortisone, a glucocorticoid, is also related to proteins but not by the enhancement of cAMP production. Hydrocortisone is transported by simple diffusion across the membrane of the cell into the cytoplasm and binds to a specific receptor The steroid-receptor complex is activated and enters the nucleus, where it regulates transcription of specific gene sequences into ribonucleic acid (RNA). Eventually, messenger RNA (mRNA) is translated to form specific proteins in the cytoplasm that are involved in the steroid-induced cellular response. 

All corticosteroids have the same general mechanism of action they traverse cell membranes and bind to a specific cytoplasmic receptor. The steroid-receptor complex translocates to the cell nucleus, where it attaches to nuclear binding sites and initiates synthesis of messenger ribonucleic acid (mRNA). The novel proteins that are formed may exert a variety of effects on cellular functions. The precise mechanisms whereby the corticosteroids exert their therapeutic benefit in asthma remain unclear, although the benefit is likely to be due to several actions rather than one specific action and is related to their ability to inhibit inflammatory processes. At the molecular level, corticosteroids regulate the transcription of a number of genes, including those for several cytokines. 

The steroid-receptor complex remains in the nucleus for a limited time only, and eventually dissociates from the chromatin. About 40% of the receptors released in this dissociation are recycled and used again the rest are destroyed and resynthesized. Steroid hormones can even regulate the level of synthesis of their own receptors, and sometimes the synthesis of other steroid receptors as well. 

Most of the established pharmacological effects of glucocorticoids are mediated by cytoplasmic glucocorticoid receptors. After binding to the receptor, the steroid-receptor complex binds to chromatin and stimulate the formation of mRNA. The mRNA stimulates the synthesis of enzymes which produce various pharmacological actions. 

Cytosolic Hormone Receptors. Steroid hormones typically bind to protein receptors, which are located directly within the cytosol (see Fig. 28-2).17 Of course, this means that the hormone must first enter the cell, which is easily accomplished by the steroid hormones because they are highly lipid soluble. After entering the cell, the hormone initiates a series of events that are depicted in Figure 28-3. Basically, the hormone and receptor form a large activated steroid-receptor complex.17 This complex travels to the cell s nucleus, where it binds to specific genes located within the DNA sequence.31,40 This process initiates gene expres-... 

FIGURE 28-3 Sequence of events of steroid hormone action. [1] Steroid hormone enters the cell, binds to a oytosolio receptor, and creates an activated steroid-receptor complex CS-FT). C2] S-R complex travels to the cell s nucleus, where it binds to specific gene segments on nuclear chromatin. [3] DNA undergoes transcription into messenger RNA (mRNA) units. (4) mRNA undergoes translation in the cytosol into specific proteins that alter cell function. 

The mechanisms of action of steroid hormones on lymphoid, mammary, and prostatic cancer have been partially clarified. Specific cell surface receptors have been identified for estrogen, progesterone, corticosteroids, and androgens in neoplastic cells in these tissues. As in normal cells, steroid hormones also form an intracellular steroid-receptor complex that ultimately binds directly to nuclear proteins associated with DNA to activate transcription of a broad range of cellular genes involved in cell growth and proliferation (see Chapter 39 Adrenocorticosteroids Adrenocortical Antagonists). 

Situations occur in which receptors are present in cells which are hormone insensitive. This is relatively common in tumour cells where our ignorance as to the molecular mechanisms involved are covered by the use of the term post receptor defect [27,28]. In at least one such case, this defect lies within the steroid response element of the gene [28]. This regulatory region usually, but not always, found 5 to the RNA initiation site, is the DNA acceptor site(s) for the steroid receptor complex (Fig. 4). It has the properties of an enhancer (see other articles for more com-... 

Fig. 1. A model for the mechanism whereby steroid hormones regulate rates of gene transcription. Steroids (S) bind with receptors (R) to form a steroid-receptor complex that interacts with DNA sequences called hormone response elements (HRE). These HREs are at variable distances from the gene promoter which frequently consists of upstream promoter elements (UPE) and conserved elements such as TATA box (TATA).

It has been established that steroid binding and activation of receptor results in increased affinity of steroid-receptor complex for sites within nuclei in vivo and for DNA in vitro [4], Such binding is low affinity, non-saturable and lacks DNA sequence specificity, yet clearly steroids regulate the transcription of specific genes. Since any protein which interacts with a specific DNA sequence must also interact with other sequences, albeit with reduced affinities, it is assumed that non-specific... 

Information on the rate of synthesis or turnover of receptors can be obtained from studies with dense amino acids, e.g., in studies with cultured cells. The isolated steroid receptor complexes are separated by density gradient centrifugation and the presence of a faster sedimenting form of the receptor, containing the dense ami-noacids is monitored [25],... 

In early studies partial purification of oestrogen and progestin receptors was achieved with ammonium sulphate precipitation and DEAE-Sephadex chromatography. Thus, partial purification of oestrogen, progestin and glucocorticoid receptors [26] has been reported. In more recent work HPLC has been used for separation on basis of ion exchange properties of intact steroid-receptor complexes [27], The con-... 

Unlike the estrogen, progesterone and glucocorticoid receptors, it appears that the l,25(OH)2D3 steroid-receptor complex does not require a temperature-de-pendent transformation step, i.e., the binding of l,25(OH)2D3 does not appear to result in a dramatic change in the shape and size of the receptor. It has recently been demonstrated, however, that the binding of l,25(OH)2D3 to its receptor exhibits positive cooperativity the binding of one molecule of l,25(OH)2D3 to the re-... 

It hus been proposed that the lysine residues ore found at the site where the steroid binds to the receptor and where the receptor binds DNA. Thus, pyridoxal S-phosphate decreases the number of receptors able to bind with the steroids and the number of steroid-receptor complexes binding to DNA. The overall result is decreased expression of DNA. 

Steroid receptor complexes, structure of. 77.3 Steroid rcccpionj, 770-773. 772f sifuciure of. 772. 772f types of. 773... 

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