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Steroid hormone receptor: Wikis

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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. Some steroid hormone receptors are part of the nuclear receptor family that include a group of homologous structured receptors (type II receptors) that bind to non-steroid ligands such as thyroid hormones and vitamin A, as well as to vitamin D, and orphan receptors. All these receptors are 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. A new class of steroid hormone receptors has recently been elucidated and these new receptors are found on the plasma membrane. New studies suggest that along with the well documented intracellular receptors that plasma membrane receptors are present for several steroid hormones and that their cellular responses are much quicker than the intracellular receptors.[1] Steroid hormone plasma membrane receptors have been described so far for aldosterone and testosterone and may lead to novel drugs targets in the future.

Contents

Types

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 (PDB: 1HCQ) where zinc is coordinated with four cysteine and no histidine residues. Their secondary and tertiary structure is distinct from that of classic zinc fingers.[2] 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.

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 receptors have no hsp, and in contrast to the classical type I receptor are located in the cell nucleus.

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.[3]

Steroid hormone receptors can also function outside of the nucleus and couple to cytoplasmic signal transduction proteins such as PI3k and Akt kinase.[4]

Functioning

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 transcription factors, augmenting or suppressing transcription of particular genes by its action on DNA. As a result messenger RNA is produced that exits the nucleus and interacts with ribosomes. There, after translation of the genetic message, specific proteins are produced. These specific proteins perform a biological task.

Type II receptors are located in the nucleus. Thus their ligands pass through the cell wall and cytoplasm and enter the nucleus, where they activated 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.

The plasma 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).

A key feature of steroid hormone receptors that is likely to provide a target for therapy confined to one tissue, is the capability of specific parts of the receptor to interact with proteins which have important roles in regulation of cell physiology[5].

See also

References

  1. ^ Norman et al., Nature Reviews Drug Discovery, 2004
  2. ^ Evans, R.M. The steroid and thyroid hormone receptor superfamily. Science 240:889-895. 1988. PMID 3283939.
  3. ^ Luconi M, Francavilla F, Porazzi I, Macerola B, Forti G, Baldi E. Human spermatozoa as a model for studying membrane receptors mediating rapid nongenomic effects of progesterone and estrogens. Steroids 2004;69:553-9. PMID 15288769.
  4. ^ Aquila S, Sisci D, Gentile M, Middea E, Catalano S, Carpino A, Rago V, Ando S. Estrogen receptor (ER)alpha and ER beta are both expressed in human ejaculated spermatozoa: evidence of their direct interaction with phosphatidylinositol-3-OH kinase/Akt pathway. J Clin Endocrinol Metab 2004;89:1443-51. PMID 15001646.
  5. ^ Copland JA, Sheffield-Moore M, Koldzic-Zivanovic N, Gentry S, Lamprou G, Tzortzatou-Stathopoulou F, Zoumpourlis V, Urban RJ, Vlahopoulos SA. Sex steroid receptors in skeletal differentiation and epithelial neoplasia: is tissue-specific intervention possible? Bioessays. 2009 Jun;31(6):629-41. Review. PMID: 19382224

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