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). In addition to nuclear receptors, several G protein-coupled receptors and ion channels act as cell surface receptors for certain steroid hormones.
Steroid receptors of the nuclear receptor family are all transcription factors. Depending upon the type of receptor, they are either located in the cytosol and move to the cell nucleus upon activation, or remain in the nucleus waiting for the steroid hormone to enter and activate them. This uptake into the nucleus is facilitated by nuclear localization signal (NLS) found in the hinge region of the receptor. This region of the receptor is covered up by heat shock proteins (HSPs) which bind the receptor until the hormone is present. Upon binding by the hormone the receptor undergoes a conformational change releasing the HSP, and the receptor together with the bound hormone enter the nucleus to act upon transcription.
This list is incomplete, as it does not include the seco-steroid calcitriol (vitamin D):
- Nuclear receptors
- Subfamily 3: Estrogen Receptor-like
- Group A: Estrogen receptor (Sex hormones: Estrogen)
- Group B: Estrogen related receptor
- Group C: 3-Ketosteroid receptors
- Subfamily 3: Estrogen Receptor-like
Intracellular steroid hormone receptors share a common structure of four units that are functionally homologous, so-called "domains":
- Variable domain: It begins at the N-terminal and is the most variable domain between the different receptors.
- 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).
- Hinge region: This area controls the movement of the receptor to the nucleus.
- 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.
Mechanism of action
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 membrane 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.
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.
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
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).
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.
- Dahlman-Wright K, Cavailles V, Fuqua SA, Jordan VC, Katzenellenbogen JA, Korach KS, Maggi A, Muramatsu M, Parker MG, Gustafsson JA (December 2006). "International Union of Pharmacology. LXIV. Estrogen receptors". Pharmacol. Rev. 58 (4): 773–81. doi:10.1124/pr.58.4.8. PMID 17132854.
- Lu NZ, Wardell SE, Burnstein KL, Defranco D, Fuller PJ, Giguere V, Hochberg RB, McKay L, Renoir JM, Weigel NL, Wilson EM, McDonnell DP, Cidlowski JA (December 2006). "International Union of Pharmacology. LXV. The pharmacology and classification of the nuclear receptor superfamily: glucocorticoid, mineralocorticoid, progesterone, and androgen receptors". Pharmacol. Rev. 58 (4): 782–97. doi:10.1124/pr.58.4.9. PMID 17132855.
- Schwabe JW, Chapman L, Finch JT, Rhodes D (November 1993). "The crystal structure of the estrogen receptor DNA-binding domain bound to DNA: how receptors discriminate between their response elements". Cell 75 (3): 567–78. doi:10.1016/0092-8674(93)90390-C. PMID 8221895. ;
- Evans RM (May 1988). "The steroid and thyroid hormone receptor superfamily". Science 240 (4854): 889–95. doi:10.1126/science.3283939. PMID 3283939.
- Mangelsdorf DJ, Thummel C, Beato M, Herrlich P, Schutz G, Umesono K, Blumberg B, Kastner P, Mark M, Chambon P, Evans RM (1995). "The nuclear receptor superfamily: the second decade". Cell 83 (6): 835–9. doi:10.1016/0092-8674(95)90199-X. PMID 8521507.
- Novac N, Heinzel T (2004). "Nuclear receptors: overview and classification". Curr Drug Targets Inflamm Allergy 3 (4): 335–46. doi:10.2174/1568010042634541. PMID 15584884.
- Luconi M, Francavilla F, Porazzi I, Macerola B, Forti G, Baldi E (August 2004). "Human spermatozoa as a model for studying membrane receptors mediating rapid nongenomic effects of progesterone and estrogens". Steroids 69 (8–9): 553–9. doi:10.1016/j.steroids.2004.05.013. PMID 15288769.
- Aquila S, Sisci D, Gentile M, Middea E, Catalano S, Carpino A, Rago V, Andò S (March 2004). "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. 89 (3): 1443–51. doi:10.1210/jc.2003-031681. PMID 15001646.
- Norman AW, Mizwicki MT, Norman DP (January 2004). "Steroid-hormone rapid actions, membrane receptors and a conformational ensemble model". Nat Rev Drug Discov 3 (1): 27–41. doi:10.1038/nrd1283. PMID 14708019.
- Maggiolini M, Picard D (February 2010). "The unfolding stories of GPR30, a new membrane-bound estrogen receptor". J. Endocrinol. 204 (2): 105–14. doi:10.1677/JOE-09-0242. PMID 19767412.
- Majewska MD, Harrison NL, Schwartz RD, Barker JL, Paul SM (1986). "Steroid hormone metabolites are barbiturate-like modulators of the GABA receptor". Science 232 (4753): 1004–7. doi:10.1126/science.2422758. PMID 2422758.
- Herd MB, Belelli D, Lambert JJ (2007). "Neurosteroid modulation of synaptic and extrasynaptic GABAA receptors". Pharmacology & Therapeutics 116 (1): 20–34. doi:10.1016/j.pharmthera.2007.03.007. PMID 17531325.
- Hosie AM, Wilkins ME, da Silva HM, Smart TG (2006). "Endogenous neurosteroids regulate GABAA receptors through two discrete transmembrane sites". Nature 444 (7118): 486–9. doi:10.1038/nature05324. PMID 17108970.
- Puia G, Santi MR, Vicini S, Pritchett DB, Purdy RH, Paul SM, Seeburg PH, Costa E (1990). "Neurosteroids act on recombinant human GABAA receptors". Neuron 4 (5): 759–65. doi:10.1016/0896-6273(90)90202-Q. PMID 2160838.
- Wu FS, Gibbs TT, Farb DH (1991). "Pregnenolone sulfate: a positive allosteric modulator at the N-methyl-D-aspartate receptor" (abstract). Mol. Pharmacol. 40 (3): 333–6. PMID 1654510.
- Maurice T, Junien JL, Privat A (1997). "Dehydroepiandrosterone sulfate attenuates dizocilpine-induced learning impairment in mice via sigma 1-receptors". Behav. Brain Res. 83 (1–2): 159–64. doi:10.1016/S0166-4328(97)86061-5. PMID 9062676.
- Strünker T, Goodwin N, Brenker C, Kashikar ND, Weyand I, Seifert R, Kaupp UB (March 2011). "The CatSper channel mediates progesterone-induced Ca2+ influx in human sperm". Nature 471 (7338): 382–6. doi:10.1038/nature09769. PMID 21412338. Lay summary – Nature News.
- Lishko PV, Botchkina IL, Kirichok Y (March 2011). "Progesterone activates the principal Ca2+ channel of human sperm". Nature 471 (7338): 387–91. doi:10.1038/nature09767. PMID 21412339.
- Rosner W, Hryb DJ, Kahn SM, Nakhla AM, Romas NA (March 2010). "Interactions of sex hormone-binding globulin with target cells". Mol. Cell. Endocrinol. 316 (1): 79–85. doi:10.1016/j.mce.2009.08.009. PMID 19698759.
- MBC 3320 Steroid hormones and receptors, by Dr. William S. Messer, updated on Monday, April 3, 2000 at 6:05 p.m.
- Steroid Hormone Receptor Signaling. Transcript from Ed. Ralph, A. Bradshaw and Edward A. Dennis: Handbook of Cell Signaling. Academic press, CA, chapter 275. ISBN 0-12-124546-2. Retrieved on May 25, 2005 at 7:49 a.m. (UTC).
- Steroid Receptors at the US National Library of Medicine Medical Subject Headings (MeSH)