Steroid hormone receptor

Steroid hormone receptors are found on the plasma membrane, in the cytosol and also in the nucleus of target cells. They are generally intracellular receptors (typically cytoplasmic) and initiate signal transduction for steroid hormones which lead to changes in gene expression over a time period of hours to days. The best studied steroid hormone receptors are members of the nuclear receptor subfamily 3 (NR3) that include receptors for estrogen (group NR3A) and 3-ketosteroids (group NR3C).

Nuclear receptors
Steroid receptors of the nuclear receptor family are all transcription factors. Depending upon the intracellular steroid hormone that they bind, they are either located in the cytosol and move to the cell nucleus upon activation, or spend their life in the nucleus waiting for the steroid hormone to enter and activate them. This uptake into the nucleus has to do with Nuclear Localization Signals (NLS) found in a region of the receptor. In most cases this signal is covered up by heat shock proteins (hsp) which bind the receptor until the hormone is present. Upon binding by the hormone the receptor undergoes a conformational change, the hsp come off, and the receptor together with the bound hormone enter the nucleus to act upon transcription.


 * Nuclear receptors
 * Subfamily 3: Estrogen Receptor-like
 * Group A: Estrogen receptor	(Sex hormones: Estrogen)
 * 1: Estrogen receptor-α	(ERα; NR3A1, )
 * 2: Estrogen receptor-β	(ERβ; NR3A2, )
 * Group B: Estrogen related receptor
 * 1: Estrogen-related receptor-α	(ERRα; NR3B1, )
 * 2: Estrogen-related receptor-β	(ERRβ; NR3B2, )
 * 3: Estrogen-related receptor-γ	(ERRγ; NR3B3, )
 * Group C: 3-Ketosteroid receptors
 * 1: Glucocorticoid receptor	(GR; )	(Cortisol)
 * 2: Mineralocorticoid receptor	(MR; )	(Aldosterone)
 * 3: Progesterone receptor	(PR; NR3C3, )	(Sex hormones: Progesterone)
 * 4: Androgen receptor	(AR; NR3C4, )	(Sex hormones: Testosterone)

Structure
Intracellular steroid hormone receptors share a common structure of four units that are functionally homologous, so-called "domains":


 * 1) Variable domain: It begins at the N-terminal and is the most variable domain between the different receptors.
 * 2) DNA binding domain: This centrally located highly conserved DNA binding domain (DBD) consists of two non-repetitive globular motifs where zinc is coordinated with four cysteine and no histidine residues. Their secondary and tertiary structure is distinct from that of classic zinc fingers. This region controls which gene will be activated. On DNA it interacts with the hormone response element (HRE).
 * 3) Hinge region: This area controls the movement of the receptor to the nucleus.
 * 4) Hormone binding domain: The moderately conserved ligand-binding domain (LBD) can include a nuclear localization signal, amino-acid sequences capable of binding chaperones and parts of dimerization interfaces. Such receptors are closely related to chaperones (namely heat shock proteins hsp90 and hsp56), which are required to maintain their inactive (but receptive) cytoplasmic conformation. At the end of this domain is the C-terminal. The terminal connects the molecule to its pair in the homodimer or heterodimer. It may affect the magnitude of the response.

Genomic
Depending on their mechanism of action and subcellular distribution, nuclear receptors may be classified into at least two classes. Nuclear receptors that bind steroid hormones are all classified as type I receptors. Only type I receptors have a heat shock protein (hsp) associated with the inactive receptor that will be released when the receptor interacts with the ligand. Type I receptors may be found in homodimer or heterodimer forms. Type II nuclear receptors have no hsp, and in contrast to the classical type I receptor are located in the cell nucleus.

Free (that is, unbound) steroids enter the cell cytoplasm and interact with their receptor. In this process heat shock protein is dissociated, and the activated receptor-ligand complex is translocated into the nucleus.

After binding to the ligand (steroid hormone), steroid receptors often form dimers. In the nucleus, the complex acts as a transcription factor, augmenting or suppressing transcription particular genes by its action on DNA.

Type II receptors are located in the nucleus. Thus, their ligands pass through the cell wall and cytoplasm and enter the nucleus where they activate the receptor without release of hsp. The activated receptor interacts with the hormone response element and the transcription process is initiated as with type I receptors.

Non-genomic
The cell membrane aldosterone receptor has shown to increase the activity of the basolateral Na/K ATPase, ENaC sodium channels and ROMK potassium channels of the principal cell in the distal tubule and cortical collecting duct of nephrons (as well as in the large bowel and possibly in sweat glands).

There is some evidence that certain steroid hormone receptors can extend through lipid bilayer membranes at the surface of cells and might be able to interact with hormones that remain outside of cells.

Steroid hormone receptors can also function outside of the nucleus and couple to cytoplasmic signal transduction proteins such as PI3k and Akt kinase.

Other
A new class of steroid hormone receptors has recently been elucidated and these new receptors are found on the cell membrane. New studies suggest that along with the well documented intracellular receptors that cell membrane receptors are present for several steroid hormones and that their cellular responses are much quicker than the intracellular receptors.

G protein-coupled receptors
At least one G protein-coupled receptor, GPR30 has been found to function a steroid receptor. GPR30 binds to and is activated by estrogen.

Ion channels
Neuroactive steroids bind to and modulate the activity of several ion channels including the GABAA,   NMDA, and sigma receptors.

The steroid progesterone has been found to modulate the activity of CatSper (cation channels of sperm) voltage-gated Ca2+ channels. Since eggs release progesterone, sperm may use progesterone as a homing signal to swim toward eggs (chemotaxis).

SHBG/SHBG-R complex
Sex hormone-binding globulin (SHBG) is thought to mainly function as a transporter and reservoir for the estradiol and testosterone sex hormones. However it has also been demonstrated that SHBG can bind to a cell surface receptor (SHBG-R). The SHBG-R has not been completely characterized. A subset of steroids are able to bind to the SHBG/SHBG-R complex resulting in an activation of adenylyl cyclase and synthesis of the cAMP second messenger. Hence the SHBG/SHBG-R complex appears to act as a transmembrane steroid receptor that is capable of transmitting signals to the interior of cells.