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regulation of gene expression by steroid hormone receptor

Image: “Regulation of gene expression by steroid hormone receptor.” by Ali Zifan 03:07, 10 July 2016 (UTC) – Own work; Used information from: Campbell Biology (10th Edition) by: Jane B. Reece & Steven A. Wasserman. License: CC BY-SA 4.0

Synthesis of Steroid Hormones

Steroid hormones are produced in the adrenal cortex, testis, ovary and some peripheral tissues (adipose tissue). They are synthesized from cholesterol and they cannot be stored owing to their lipophilic nature. This is the reason for their immediate release from the cell as soon as they are synthesized.

Difference Between the Peptide Hormone and the Steroid Receptor

The steroid hormone can easily enter the target cell by crossing the cell membrane (unlike peptide hormones, which basically act at the level of the plasma membrane) to exert their effect. Once entered, they directly interact with cytoplasmic or nuclear receptors and the hormone-receptor complex then activates DNA. The activation of the DNA can have many fold effects from the activation of the transcription of the DNA leading to the synthesis of a particular protein or to the repression of some region of DNA.

Compared to peptide hormones, steroid hormones are slower acting and have relatively longer half-lives. Examples of steroid hormones include cortisol, estrogen, and testosterone.
Steroids play important roles in carbohydrate metabolism (glucocorticoids), mineral balance (mineralocorticoids), reproductive functions (gonadal steroids). They also play important roles in inflammatory responses, stress responses, bone metabolism, behavioral, emotional and cognitive processes.

Mechanism of Action of Steroid Hormone Receptors

Steroid hormone receptors are intracellular and prior to hormone binding may be located in the cytoplasm or in the nucleus. In the cytoplasm, after attachment of the steroid hormone, the complex moves to the nucleus where it carries on its action. Or the receptor may be located in the nucleus prior to binding. In either case, after binding the action occurs in the nucleus by DNA modification.

Predominantly cytoplasmic Predominantly nuclear
  • Glucocorticoid receptor
  • Mineralocorticoid receptor
  • Androgen receptor
  • Estrogen receptor
  • Thyroid hormone receptor
  • Vitamin D receptor
  • Retinoic acid receptor

The entry of the hormone-receptor complex into the nucleus is brought about by a specific part of the receptor known as the nuclear localization signal (NLS).

The entry of the unbound receptor into the nucleus without the hormone is avoided by the coverage of the localization signal areas by heat shock proteins. Upon binding of the hormone, the heat shock protein gets liberated leading to the exposure of the nuclear localization signal, which in turn helps in the movement of the hormone receptor complex into the nucleus.

In addition to this, the binding of the hormone to the hormone receptor brings about a series of conformational changes in the receptor.

The hormone-receptor complex that forms as a result, binds specifically to promoter and enhancer elements of the DNA, thereby affecting the expression of specific target genes.
The binding of the hormone receptor complex to the specific part of the DNA occurs via a specialized domain of the receptor called Zinc finger. The binding of the Zinc finger causes modulation of the DNA. The further outcome of the binding is determined by the specific co-activator and the co-repressor, which bind to the complex.

Molecular Structure of the Steroid Hormone Receptor

nuclear receptor structure

Image: “Structural Organization of Nuclear Receptors.” by Boghog2 – Created myself using public domain software PyMol. License: Public Domain

Broadly, the intracellular hormone receptor consists of four domains namely the variable domain, the DNA binding domain, hormone binding domain, and the hinge region. These are the four units which form a common structure of all the intracellular steroid hormone receptors.

The names of the subunits mirror their function. The function of the DNA binding region is to bind with the DNA. This centrally located highly conserved DNA binding domain (DBD) consists of two non-repetitive globular motifs where zinc is coordinated with four cysteine residues. Their secondary and tertiary structure is distinct from that of classic zinc fingers. This region controls which gene will be activated. This is the region which interacts with the hormone-responsive elements in the DNA (HRE).
The hinge region plays a prominent role in the movement of the hormone receptor complex into the nucleus.

The variable region begins at the N-terminal and is the region where the sequence of amino acids is variable among the different receptors.

The hormone binding domain consists of the ligand binding domain, the localization signals and sequence for binding with the heat shock proteins. These heat shock proteins (namely heat shock proteins hsp90 and hsp56),  are required to maintain their inactive (but receptive) cytoplasmic conformation and are described by a special name known as chaperones.

Examples of the receptor

Hormones that bind to steroid hormone receptors include the steroids (such as estrogen, progesterone, glucocorticoids), some amine hormones (such as thyroxines) and the retinoids.
The binding as discussed can be either at the cytoplasmic or at the nuclear level. Steroid hormone receptors that are predominantly cytoplasmic include the receptors for mineralocorticoids, glucocorticoids, and androgen hormones. Steroid hormone receptors that are predominantly nuclear include estrogen receptor, thyroid hormone receptor, vitamin D receptor, and retinoic acid receptor.

The nuclear receptors subfamily 3 and the 3 keto-steroid receptors are the two most commonly studied steroid hormone receptor families. The receptors of the estrogen groups form the NR3A members.

It should also be remembered that steroid hormones can also act through other receptors such as G protein-coupled receptor in addition to steroid hormone receptors.

Classification of the Nuclear Receptors

The nuclear–receptors–subfamily3 is divided into group A and group C. The group A is divided into two, namely the estrogen receptor alpha and the estrogen receptor beta.
Group C is also known as the 3keto-steroid receptor group, which in turn consists of subgroups:  1=glucocorticoid,  2=mineralocorticoid,  3=progesterone, and 4=androgen receptor.

Classification based on the mechanism of action

Depending on their mechanism of action and subcellular distribution, nuclear receptors may be classified into at least two classes. The basic difference between the two types is the presence of heat shock proteins. While type 1 contains a heat shock protein bound with the inactive receptor and resides in the cytosol, type 2 resides in the nucleus and has no heat shock protein but in the absence of its steroid hormone ligand, type 2 nuclear receptors are often complexed with corepressor proteins. Ligand binding to the nuclear receptor causes dissociation of corepressor and recruitment of coactivator proteins. Type II nuclear receptors include principally subfamily 1, for example, the retinoic acid receptor, retinoid X receptor, and thyroid hormone receptor.

The intricacies on binding with the steroid hormones have already been described in the mechanism of action. The latest discoveries in this field have also identified other types of nuclear receptors namely type 3 and type 4. Type 3 is basically variant of type 1 and type 4 basically is a monomer unit which binds to DNA (rather than the heterodimer).

nuclear receptor action type 1

Image: “Mechanism of class I nuclear receptor action. A class I nuclear receptor (NR), in the absence of ligand, is located in the cytosol. Hormone binding to the NR triggers dissociation of heat shock proteins (HSP), dimerization, and translocation to the nucleus, where the NR binds to a specific sequence of DNA known as a hormone response element (HRE). The nuclear receptor DNA complex, in turn, recruits other proteins that are responsible for transcription of downstream DNA into mRNA, which is eventually translated into protein, which results in a change in cell function.” by Boghog2 – Made by Boghog2. License: Public Domain

type 2 nuclear receptor action

Image: “Mechanism of class II nuclear receptor action. A class II nuclear receptor (NR), regardless of ligand-binding status, is located in the nucleus bound to DNA. For the purpose of illustration, the nuclear receptor shown here is the thyroid hormone receptor (TR) heterodimerized to the RXR. In the absence of ligand, the TR is bound to corepressor protein. Ligand binding to TR causes dissociation of corepressor and recruitment of coactivator protein, which, in turn, recruits additional proteins such as RNA polymerase that are responsible for transcription of downstream DNA into RNA and eventually protein.” by Boghog2 – Own work. License: Public Domain

It should be noted that both type 1 and type 2 ultimately are related to the genomic DNA for the manifestation of their action and there is another group, which manifests the non-genomic structures. Nuclear receptors in non-genomic structures are membrane-associated instead of being localized in the cytosol or nucleus. These membrane-associated receptors function through alternative signal transduction mechanisms not involving gene regulation.
The aldosterone receptors which come under this, are located in the tubule of the kidney and their function is to modulate the action of the aldosterone which binds with them. On binding of aldosterone, the activity of the Na + K+ ATPase on the basolateral membrane is increased.

In addition to this, the epithelial sodium channels, the ROMK potassium channels are also activated. Some of the hormone receptors are coupled with the signals process in the cytoplasm rather than the action of the gene level in the nucleus.

Co-regulatory Proteins

There are two types of co-regulatory proteins namely the coactivator and the corepressor. The binding of the nuclear receptor to the response element in the DNA recruites a number of other proteins.

These proteins can have various functions ranging from chromatin remodeling to acting as bridging molecules. Generally, the coactivators have intrinsic histone acetyltransferase activity whereas the corepressors recruit the histone deacetylase activity. The coactivators are generally recruited by the agonist ligand and the corepressors are generally recruited by the antagonist ligand.

Special Forms of Steroid Hormone Receptors

The sex hormone binding globulin which generally functions in the transport mechanism has shown to be linked with the cell membrane of the cells in some of the cases, leading to the manifestation of the action of the steroid hormone. The sex hormone binding globulin thus acts as a form of receptor with manifestation based on the characteristic of the hormone which binds with it.

GPR30 is a form of G protein-coupled receptor which functions as a steroid hormone receptor and the steroid hormone which it binds is estrogen. It is well known that in the central nervous system the neurosteroid that can bind to the GABA channels at the glutamate NMDA receptor. Progesterone acts at one of the most important cation channels in the sperm which modulate the motility of the sperm known as the CATSPAR channel.

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