Steroid Actions


Cross references: 
Steroids    Hormones in General
 
Intracellular Receptors   Testosterone Receptor  
 
Testosterone Transcription Factor     


Hormones and Behavior : Neuroactive Steroid Actions at the GABAA Receptor (Goog) 


Mechanism of Action: Hormones with Intracellular Receptors
(Goog:"steroid receptors") 
This is just one small section of an entire book published online by Colorado State University.  Highly recommended.   
 
    "
Receptors for steroid and thyroid hormones are located inside target cells, in the cytoplasm or nucleus, and function as ligand-dependent transcription factors.
  That is to say, the hormone-receptor complex binds to promoter regions of responsive genes and stimulates, or sometimes inhibits, transcription from those genes." 
    "
Thus, the mechanism of action of steroid hormones is to modulate gene expression in target cells. By selectively affecting transcription from a battery of genes, the concentration of those respective proteins are altered, which clearly can change the phenotype of the cell.
"

Structure of Intracellular Receptors

     "Steroid and thyroid hormone receptors are members of a large group ("superfamily") of transcription factors. In some cases, multiple forms of a given receptor are expressed in cells, adding to the complexity of the response. All of these receptors are composed of a single polypeptide chain that has, in the simplist analysis, three distinct domains:
  • The amino-terminus: In most cases, this region is involved in activating or stimulating transcription by interacting with other components of the transcriptional machinery. The sequence is highly variable among different receptors.
  • DNA binding domain: Amino acids in this region are responsible for binding of the receptor to specific sequences of DNA.
  • The carboxy-terminus or ligand-binding domain: This is the region that binds hormone.
     In addition to these three core domains, two other important regions of the receptor protein are a nuclear localization sequence, which targets the the protein to nucleus, and a dimerization domain, which is responsible for latching two receptors together in a form capable of binding DNA.

Hormone-Receptor Binding and Interactions with DNA

    "Being lipids, steroid hormones enter the cell by simple diffusion across the plasma membrane. Thyroid hormones enter the cell by facilitated diffusion. The receptors exist either in the cytoplasm or nucleus, which is where they meet the hormone. When hormone binds to receptor, a characteristic series of events occurs:
  • Receptor activation is the term used to describe conformational changes in the receptor induced by binding hormone. The major consequence of activation is that the receptor becomes competent to bind DNA.
  • Activated receptors bind to "hormone response elements", which are short specific sequences of DNA which are located in promoters of hormone-responsive genes. In most cases, hormone-receptor complexes bind DNA in pairs, as shown in the figure below.
  • Transcription from those genes to which the receptor is bound is affected. Most commonly, receptor binding stimulates transcription. The hormone-receptor complex thus functions as a transcription factor.

    "As might be expected, there are a number of variations on the themes described above, depending on the specific receptor in question. For example, in the absense of hormone, some intracellular receptors do bind their hormone response elements loosely and silence transcription, but, when complexed to hormone, become activated and strongly stimulate transcription. Some receptors bind DNA not with another of their kind, but with different intracellular receptor."   

    "As a specific example, consider glucocorticoids, a type of steroid hormone that probably affects the physiology of all cells in the body. The image below depicts a pair of glucocorticoid receptors (blue and green on the top) bound to their DNA hormone response element (bottom). The two steroid hormones are not visible in this depiction."  












My comments

1. 
Apparently it's the receptor, acting as a transcription factor, that determines which section of DNA is activated by the steroid. 
2.  Since "
(I)n some cases, multiple forms of a given receptor are expressed in cells... ", a single hormone, such as testosterone, can activate more than one transcription factor in a cell at a time and therefore promote the transcription of more than one set of genes in a cell at a time.     
3.  This is a small section of a much larger and very interesting online course offered in fairly non-technical language.   
4.  Internet searches require appropriate search terms, and it was this link that provided me with the search term: "transcription factor". 


Transcription factor (Wiki)   
Is it the transcription factors that determine which section of the DNA gets transcribed? 
    "
Other transcription factors differentially regulate the expression of various genes by binding to enhancer regions of DNA adjacent to regulated genes. These transcription factors are critical to making sure that genes are expressed in the right cell at the right time and in the right amount, depending on the changing requirements of the organism.

My comment
This appears to be my answer.   


Enhancer (genetics) (Wiki)   
    "In genetics, an enhancer is a short region of DNA that can be bound with proteins (namely, the trans-acting factors, much like a set of transcription factors) to enhance transcription levels of genes (hence the name) in a gene cluster.

File:Gene enhancer.svg 
    "
While enhancers are usually cis-acting, an enhancer does not need to be particularly close to the genes it acts on, and need not be located on the same chromosome.[1] In eukaryotic cells the structure of
the chromatin complex of DNA is folded in a way that functionally mimics the supercoiled state characteristic of prokaryotic DNA, so that although the DNA is far from the genes in nucleotides, it is geometrically close to the promoter and gene. This allows it to interact with the general transcription factors and RNA polymerase II. An enhancer may be located upstream or downstream of the gene that it regulates. Furthermore, an enhancer does not need to be located near to the transcription initiation site to affect the transcription of a gene, as some have been found to bind several hundred thousand base pairs upstream or downstream of the start site. Enhancers do not act on the promoter region itself, but are bound by activator proteins. These activator proteins interact with the mediator complex, which recruits polymerase II and the general transcription factors which then begin transcribing the genes. Enhancers can also be found within introns. An enhancer's orientation may even be reversed without affecting its function. Additionally, an enhancer may be excised and inserted elsewhere in the chromosome, and still affect gene transcription. That is the reason that intron polymorphisms are checked though they are not translated.
"
My comment
I'm beginning to think that I need to learn a little bit more about genetics.  For the moment, I'm furthering my education by following the links, above. 

Coactivation and corepression in transcriptional regulation by steroid/nuclear hormone receptors  (PubMed) 
Only abstract available online.  Full article not available online. 
    "
In the absence of hormone, unliganded receptors interact with a family of transcriptional corepressors, including SMRT and N-CoR, which target histone deacetylases to establish a condensed and repressed chromatin structure. Upon hormone binding, the corepressor complex is replaced by a coactivator complex, containing SRC1/TIF2/RAC3 and CBP/p300, which target histone acetyltransferases to generate a transcriptionally accessible chromatin structure.


From "Related citations" 


The role of coactivators and corepressors in the biology and mechanism of action of steroid hormone receptors
(PubMed) 
Only abstract available online.  I got the PDF through the library. 
  "Steroid hormone receptors are members of a superfamily of ligand-dependent transcription factors. As such they have a DNA binding domain that recognizes specific target gene sequences along with separate transcriptional activation domains. What sets steroid hormone receptors (and other nuclear hormone receptors) apart from other families of sequence specific transcriptional activators is the presence of a ligand binding domain (LBD) that acts as a molecular switch to turn on transcriptional activity when a hormonal ligand induces a conformational change in the receptor. Upon binding hormone, steroid receptors recruit a novel coactivator protein complex with an essential role in receptor-mediated transcriptional activation. Coactivators function as adaptors in a signaling pathway that transmits transcriptional responses from the DNA bound receptor to the basal transcriptional machinery."


Neuroactive steroids: mechanisms of action and neuropsychopharmacological perspectives.
  (PubMed) 
Only abstract available online. 
    "
Steroids influence neuronal function by binding to intracellular receptors that can act as transcription factors and regulate gene expression. In addition, some so-called 'neuroactive steroids' are potent modulators of an array of ligand-gated ion channels and of distinct G-protein coupled receptors via nongenomic mechanisms ... intracellular crosstalk between genomic and nongenomic steroid effects.
"



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