Steroid hormone receptor
Steroid hormone receptors are found in the nucleus, cytosol, and also on the plasma membrane of target cells. They are generally intracellular receptors (typically cytoplasmic or nuclear) 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.
- Nuclear receptors
- Subfamily 3: Estrogen Receptor-like
- Group A: Estrogen receptor (Sex hormones: Estrogen)
- 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
GPCR linked proteins most likely interact with steroid hormones through an amino acid consensus sequence traditionally thought of as a cholesterol recognition and interaction site. About a third of Class A GPCRs contain this sequence. The steroid hormones themselves are different enough from one another that they do not all affect all of the GPCR linked proteins; however, the similarities between the steroid hormones and between the receptors make plausible the argument that each receptor may respond to multiple steroid hormones or that each hormone could affect multiple receptors. This is contrary to the traditional model of having a unique receptor for each unique ligand.
At least four different GPCR-linked proteins are known to respond to steroid hormones. G Protein-Coupled Receptor 30 (GPR30) binds estrogen, Membrane Progestin Receptor (mPR) binds progesterone, G Protein-Coupled Receptor Family C Group 6 Member A (GPRC6A) binds androgens, and Thyroid Hormone and Trace Amine Associated Receptor 1 (TAAR1) binds Thyroid hormone (though not technically steroid hormones, thyroid hormones can be grouped here because their receptors belong to the nuclear receptor superfamily). As an example of the effects of these GPCR-linked proteins consider GPR30. GPR30 binds estrogen, and upon binding estrogen this pathway activates adenylyl cyclase and epidermal growth factor receptor. It results in vasodilation, renoprotection, mammary gland development, etc.
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 (Dec 2006). "International Union of Pharmacology. LXIV. Estrogen receptors". Pharmacological Reviews. 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 (Dec 2006). "International Union of Pharmacology. LXV. The pharmacology and classification of the nuclear receptor superfamily: glucocorticoid, mineralocorticoid, progesterone, and androgen receptors". Pharmacological Reviews. 58 (4): 782–97. doi:10.1124/pr.58.4.9. PMID 17132855.
- doi:10.1016/0092-8674(93)90390-C. PMID 8221895.; Schwabe JW, Chapman L, Finch JT, Rhodes D (Nov 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.
- 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, Schütz G, Umesono K, Blumberg B, Kastner P, Mark M, Chambon P, Evans RM (Dec 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 (Dec 2004). "Nuclear receptors: overview and classification". Current Drug Targets. Inflammation and Allergy. 3 (4): 335–46. doi:10.2174/1568010042634541. PMID 15584884.
- Luconi M, Francavilla F, Porazzi I, Macerola B, Forti G, Baldi E (Aug 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 (Mar 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". The Journal of Clinical Endocrinology and Metabolism. 89 (3): 1443–51. doi:10.1210/jc.2003-031681. PMID 15001646.
- Norman AW, Mizwicki MT, Norman DP (Jan 2004). "Steroid-hormone rapid actions, membrane receptors and a conformational ensemble model". Nature Reviews. Drug Discovery. 3 (1): 27–41. doi:10.1038/nrd1283. PMID 14708019.
- Wang C, Liu Y, Cao JM (2014). "G protein-coupled receptors: extranuclear mediators for the non-genomic actions of steroids". International Journal of Molecular Sciences. 15 (9): 15412–25. doi:10.3390/ijms150915412. PMC . PMID 25257522.
- Majewska MD, Harrison NL, Schwartz RD, Barker JL, Paul SM (May 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 (Oct 2007). "Neurosteroid modulation of synaptic and extrasynaptic GABA(A) 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 (Nov 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 (May 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 (Sep 1991). "Pregnenolone sulfate: a positive allosteric modulator at the N-methyl-D-aspartate receptor" (abstract). Molecular Pharmacology. 40 (3): 333–6. PMID 1654510.
- Maurice T, Junien JL, Privat A (Feb 1997). "Dehydroepiandrosterone sulfate attenuates dizocilpine-induced learning impairment in mice via sigma 1-receptors". Behavioural Brain Research. 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 (Mar 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 (Mar 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 (Mar 2010). "Interactions of sex hormone-binding globulin with target cells". Molecular and Cellular Endocrinology. 316 (1): 79–85. doi:10.1016/j.mce.2009.08.009. PMID 19698759.