Steroid Recptor

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Steroid Hormone Receptor


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1. Biological effects of steroid hormones are transduced by intracellularreceptors that directly mediate the action of their related hormone.

2. Steroid hormone receptors (SHRs) were the first recognized membersof the nuclear receptor superfamily, a class of transcription factorsregulated by small lipid-soluble molecules.

3. Initial discovery of receptors for steroid hormones in 1960s, originallythese steroid receptors were discovered in the cytosol.

4. Arrival of monoclonal antibodies to specific steroid receptor in mid1980s confirmed that glucocorticoid receptors are primarily localizedin the cystol, whereas sex steroids in the nucleus of target cell.

5. Steroid hormone receptors have also been found on the plasmamembrane of target cells.

INTRODUCTION


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TYPES OF STEROID RECEPTORS


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Steroid hormone receptors arecomposed of

1. A variable N-terminal domain(NTD, A/B)

2. A highly conserved DNABinding Domain (DBD, C)

3. A flexible hinge region (D)

4. A C-terminal Ligand BindingDomain (LBD, E)

5. The estrogen receptor isunique in that it contains anadditional C-terminal (F)domain with unknownfunction.

STRUCTURE

Nuclear receptors consist of six domains (A-F) based on regions of conserved sequenceand function. The evolutionarily conserved regions are C and E, and the divergent

regions A/B, D, and F regions.


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1. DNA-binding domain (DBD): Centrally located, well conservedamong SHRs, and comprised of two zinc-finger motifs involved inboth proteinDNA and proteinprotein contacts.

2. Ligand-binding domain (LBD): Located at the carboxy terminal

of the receptor, is moderately conserved and folds into a canonical -helical sandwich generally consisting of 12 -helices (H1 to H12).

LBD may also contain:ligand-dependent nuclear translocation signaldeterminants to bind chaperone proteins

dimerization interfacespotent ligand-dependent activation domain referred to asAF-2

ligand-independent activation domain (AF-1)encoded within the nonconserved amino-terminalregion of the receptors

STRUCTURECONTD..


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OVERVIEW OF MECHANISM OF ACTION

The lipophilic signals (steroid and their derivatives), being lipid soluble,can cross the plasma membrane and bind to specific intracellular receptorlocated either in the cytosol (for gucocorticoids) or in the nucleus (for sexsteroid, thyroid hormone, vit. D3 and retinoic acid).


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MECHANISM OF ACTIONGenomic

1. Binding of steroid and related hormone leads to a conformational

change in the receptor molecule thereby converting the non-DNAbinding form of receptor to a DNA-binding form, called activation ortransformation of the receptor.

2. Association of the heat shock proteins along with a number of otherwell characterized modulators maintain the inactive state of receptors.

3. The binding of steroids leads to the dissociation of these chaperonsthat converts the receptor into a DNA-binding form.

4. Activated steroid receptor complex interacts with specific DNAsequences, located a couple of hundreds bases upstream the regulatedgene.


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5. It modulates its expression by influencingthe synthesis of mRNAs and respectiveproteins thus producing the cellularresponse.

6. These Intracellular steroid receptors act likeligand-activated transcription factors.

7. They consist of variable N-terminus thatcontributes to the transactivation function; a

highly conserved DNA-binding Domain isresponsible for specific DNA-binding anddimerization.

8. A C-terminal domain involved in Ligand-binding, nuclear localization and ligand-dependent transactivation function.

MECHANISM OF ACTIONCONTD..


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9. Cross talk between the intracellular steroid action cascade is seenamong the protein/ peptide hormone modifiers.

10. Protein kinases are central to these cross-talks.

11. Most of the steroid receptors being phosphoproteins, theirphosphorylation might control the activation and affinity of thesereceptors to DNA response elements.

11. Selected steroid hormones can be activated in a ligand-independentmanner by membrane receptor antagonist.

Example: Dopamine has been reported to mimic the action of

progesterone in activating the progesterone receptor 8-bromo-cAMP has been demonstrated to mediate

progesterone receptor-dependent transcription in the absenceof progesterone.



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Non-Genomic

1. Receptors for steroid hormones are also located on the membranesurfaces of certain cell types such as spermatozoa, oocytes,

endometrial cells and granulosa cells.

2. Steroids influence the production of intracellular secondarymessengers such as Ca+2 and IP3 in very rapid manner.

3. These steroids actions are too fast where no mRNA and proteinsynthesis are observed.

4. The non genomic action of steroid hormone are not blocked by theinhibitors of transcription as well as translation.

5. These effects are also not abolished by the antagonists to the genomicreceptor.


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6. Such non-genomic action of steroid hormones are mediated bybinding of steroids either to its own specific cell surface receptor orthrough interaction with other protein/peptide hormone receptor.

7. If the steroid knocks at the latter, it modulates the effectiveness of theconcerned protein/peptide hormone.


9. If it knocks the former, itinfluences directly orindirectly the membranebound protein tyrosinekinases or the associatedion channels.

10. Both these culminate to acellular response.


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1. http://www.mesomorphosis.com/articles/scally/steroid-hormone-nuclear-receptors.htm

2. Steroid hormone action mechanism Ramesh Sharma

Current science 1999;Vol.76: 271-2723. Steroid Hormone Receptor SignalingHandbook of Cell Signaling

Ralph A. Bradshaw and Edward A. Dennis2003, Elsevier, Academic press, CA

4. Overview of nomenclature of nuclear receptors. Germain P, Staels B, Dacquet C, Spedding M, Laudet V.

Pharmacol Rev 2006;58:685-704.5. http://www.vivo.colostate.edu/hbooks/pathphys/endocrine/

moaction/intracell.html

REFERENCES


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1. http://www.mesomorphosis.com/articles/scally/steroid-hormone-nuclear-receptors.htm

2. Steroid hormone action mechanism Ramesh Sharma

Current science 1999;Vol.76: 271-2723. Steroid Hormone Receptor SignalingHandbook of Cell Signaling

Ralph A. Bradshaw and Edward A. Dennis2003, Elsevier, Academic press, CA

4. Overview of nomenclature of nuclear receptors. Germain P, Staels B, Dacquet C, Spedding M, Laudet V.

Pharmacol Rev 2006;58:685-704.5. http://www.vivo.colostate.edu/hbooks/pathphys/endocrine/

moaction/intracell.html

REFERENCES

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Steroid Recptor