Cytosolic steroid hormone

Steroid hormones act in a different manner from most hormones we have considered. In many cases, they do not bind to plasma membrane receptors, but rather pass easily across the plasma membrane. Steroids may bind directly to receptors in the nucleus or may bind to cytosolic steroid hormone receptors, which then enter the nucleus. In the nucleus, the hormone-receptor complex binds directly to specific nucleotide sequences in DNA, increasing transcription of DNA to RNA (Chapters 31 and 34). 

Table 11.1 Agonists and antagonists of cytosolic steroid hormone receptors...

The intracellular distribution of steroid hormone receptors has long been the object of controversy. The first theoretical formulation on the intracellular location of the ERs was elaborated by Jensen in 1968 and is known as the two-step theory. Its execution was based entirely on biochemical observations obtained by means of tritium-marked estradiol. The ERs, in cells not exposed to hormones, are found abundantly in the soluble cell fraction, or cytosol (Fig. 1.1). Treatment with hormones confines the receptors to the particulated or nuclear fraction and causes their disappearance from the cytosol. The two-step theory established that the receptor is found in the cytoplasm naturally and upon the arrival of a hormone it is transformed into a complex hormone-receptor (first step) capable of translocating itself to the nucleus and of modifying gene expression (second step). 

Fig. 1.1. General mechanism of action of steroid hormones. Steroid hormones cross through the plasmatic membrane without apparent difficulty favored by gradient. Some, which can be considered prohormones, are metabolized and transformed into more active products. This is the case with testosterone, which becomes dihydrotestosterone (DHT) in the target tissues of androgens, through the 5-alfa-reductase enzyme. The hormone binds to the receptor, a soluble protein of the cellular cytosol that, in the absence of hormone, is found associated with other proteins (hsp90 and others) that maintain the receptor in an inactive state. The hormone-receptor bond causes the other proteins to separate and a homodimer to be formed. The homodimer is the activated form of the receptor since it is capable of recognizing the genes that depend on that steroid hormone as well as of activating its expression, which leads to the synthesis of specific proteins...

Here are some insights into how l,25(OH)2D works. Like steroid hormones and retinoic acid, l,25(OH)2D binds to and activates a cytosolic receptor present in most cells of the human body. The activated receptor migrates to the cell nucleus, binds to a specific nucleotide sequence in the nuclear DNA, and acts as a transcription factor. Directly or indirectly, the expression of some 200 genes is affected as a result. 

Figure 12.8 Effector mechanism activation of a specific gene by hormone-receptor complex binding to DNA. A steroid is used to illustrate the mechanism. The hormone enters the cell and binds to its receptor (R) in the cytosol, the hormone-receptor complex enters the nucleus and binds to a specific sequence in the DNA that stimulates transcription of a gene or genes the resultant increase in mRNA increases the synthesis of specific proteins. The binding site on the DNA is specific and is usually termed a response element. Thyroxine (i.e. triiodothyronine) also uses this effector mechanism. Activation of genes, RNA processing to produce mRNA and translation are described in Chapter 20 (see Figures 20.20, 20.21 and 20.22).

An account of the principles which help to understand how hormones achieve their roles in the body is given in Chapter 12. The understanding is based on separation of the effects of hormones into three components the action, the effects (biochemical and physiological) and the function. A steroid hormone binds to a cytosolic intracellular receptor, which then moves into the nucleus where it binds to DNA at a specific site (the steroid response element) and activates genes which result in the formation of proteins that elicit biochemical and physiological effects. This is discussed for cortisol in Chapter 12 and aldosterone in Chapter 22. Much of the interest in the reproductive steroid hormones is in the physiological effects and how these account for their functions. 

The steroid hormones are distributed throughout the entire organism by means of the circulatory system. Transport often occurs in the form of a complex with a specific binding protein. An example for such a binding protein is transcortin, which is responsible for the transport of the corticosteroids. The steroid hormones enter the cell by diffusion and activate the cytosolic receptors. 

Fig. 4.10. Principle of signal transduction by steroid hormone receptors. The steroid hormone receptors in the cytosol are found in the form of an inactive complex with the heat shock proteins Hsp90 and Hsp56 and with protein p23. The binding of the hormone activates the receptor so that it can be transported into the nucleus where it binds to its cognate HRE. It remains unclear in which form the receptor is transported into the nucleus, and to which extent the associated proteins are involved in the transport. One mechanism of activation of transcription initiation involves activation of a histone acetylase and remodehng of chromatin. Furthermore, the receptors interact directly or indirectly with components of the RNA polymerase II holoenzyme (e.g. SUGl).

Effect of vitamin D on the intestine 1,25-diOH D3 stimulates intestinal absorption of calcium and phosphate. 1,25-diOH D3 enters the intestinal cell and binds to a cytosolic receptor. The 1,25-diOH D3-receptor complex then moves to the nucleus where it selectively interacts with the cellular DNA. As a result, calcium uptake is enhanced by an increased synthesis of a specific calcium-binding protein. Thus, the mechanism of action of 1,25-diOH D3 is typical of steroid hormones (see p. 238). 

Each steroid hormone diffuses across the plasma membrane of its target cell and binds to a specific cytosolic or nuclear receptor. These receptor-ligand complexes accumulate in the nucleus, dimerize, and bind to specific regulatory DIMA sequences (hormone-response elements) in association with coactivator proteins, thereby causing promoter activation and increased transcription of targeted genes. 

Because of their hydrophobic character the steroid hormones or other nonpolar ligands diffuse through membranes into cells. There they may encounter a variety of binding proteins that affect their access to a receptor.307 311 Some receptors, including glucocorticoid receptors, are found in the cytosol. After a hor-... 

Eukaryote organisms primarily respond to external signals by an initial signal perception by receptors. In general, such receptors can be either cytosolic or located on the plasma membrane [13-15]. The former mechanism applies to thyroid hormones (triiodothyronine and tetraiodothyronine or thyroxine), retinoids (e.g. retinoic acid), the insect developmental hormones such as ecdysone, steroid hormones (such as... 

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 28-2 Primary cellular locations of hormone receptors. Peptide hormones tend to bind to surface membrane receptors (site 0 steroid hormones bind to cytosolic receptors [site 10 and thyroid hormones bind to receptors in the cell nucleus [site III). 

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. 

Hormones Some lipophilic hormones (e.g. the steroid hormones, thyroxine, retinoic acid and vitamin D) diffuse across the plasma membrane and interact with intracellular receptors in the cytosol or nucleus. Other lipophilic hormones (e.g. the prostaglandins) and hydrophilic hormones (e.g. the peptide hormones insulin and glucagon and the biogenic amines epinephrine and histamine) bind to receptor proteins in the plasma membrane. 

Small lipophilic (lipid-soluble) hormones diffuse across the plasma membrane and then interact with intracellular receptors in the cytosol or nucleus. The resulting hormone-receptor complex often binds to regions of the DNA and affects the transcription of certain genes (see Topic G7). Small lipophilic hormones with intracellular receptors include the steroid hormones which are synthesized from cholesterol (see Topic K5) (e.g. the female sex hormones estrogen and progesterone), thyroxine which is produced by thyroid cells and is the principal iodinated compound in animals, retinoic acid which is derived from vitamin A, and vitamin D which is synthesized in the skin in response to sunlight (see Topic K5). 

Fig. 1. Intracellular events involved in steroid hormone action. A. Model in which the receptor is cytosolic and transfers tothe nucleus after binding with steroid (S). The cytosolic 8S receptor consists of a ligand binding unit ( ) and other units, one of which is a 90 kDa heat shock protein ( ). Activation is shown here as involving dimerisation of the ligand binding unit. This simplification of the true events applies to oestradiol receptor but not necessarily for other receptor classes. There is no agreement as to where activation occurs. B. Model in which unliganded receptor (0) is in the nucleus. A conformational change occurs on binding steroid (S) which may result in increased affinity for specific DNA sequences.

Correct answer = E. All steroid hormones bind to receptors in the nucleus or the cytosol. 

Betamethasone is a corticosteroid. Corticosteroids are very lipophilic (due to their hydrocarbon skeleton) and as a result can passively diffuse into target cells. It acts by binding to the intracellular corticosteroid receptor protein, which is found within the cytosol. The resulting complex translocates to the nucleus and induces synthesis of mediator proteins (e.g. metabolic enzymes and lipocortin). The binding of steroid hormones to their receptors causes changes in gene transcription and cell function. Corticosteroids reduce the inflammatory reaction by limiting capillary dilatation and vascular permeability. 

The steroid hormones are hydrophobic, this property enabling them to readily cross the plasma membrane to bind their respective cytosolic receptors. However, transport of such hydrophobic hormones through the blood stream requires hormone-binding proteins such as the steroid-binding globulins and corticosteroid-binding globulins. 

Table 11.2 Cytosolic non-steroid hormone receptor agonists and antagonists...

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