Nuclear receptors

Nuclear (or cytoplasmic) receptors are soluble proteins localized within the cytoplasm or the nucleoplasm. The hormone has to pass through the plasma membrane, usually by passive diffusion, to reach the receptor and initiate the signal cascade. The nuclear receptors are ligand-activated transcription activators; on binding with the ligand (the hormone), they will pass through the nuclear membrane into the nucleus and enable the production of a certain gene and, thus, the production of a protein.

The typical ligands for nuclear receptors are lipophilic hormones, with steroid hormones (for example, testosterone, progesterone and cortisol) and derivatives of vitamin A and D among them. These hormones play a key role in the regulation of metabolism, organ function, developmental processes and cell differentiation. The key value for the signal strength is the hormone concentration, which is regulated by :

- Biosynthesis and secretion of hormones in the endocrine tissue. As an example, the hypothalamus receives information, both electrical and chemical. It produces releasing factors that affect the hypophysis and make it produce glandotrope hormones which, in turn, activate endocrine organs so that they finally produce hormones for the target tissues. This hierarchical system allows for the amplification of the original signal that reached the hypothalamus. The released hormones dampen the production of these hormones by feedback inhibition to avoid overproduction.

- Availability of the hormone in the cytosol. Several hormones can be converted into a storage form by the target cell for later use. This reduces the amount of available hormone.

- Modification of the hormone in the target tissue. Some hormones can be modified by the target cell so they no longer trigger the hormone receptor (or at least, not the same one), effectively reducing the amount of available hormone.

The nuclear receptors that were activated by the hormones attach at the DNA at receptor-specific Hormone Responsive Elements (HREs), DNA sequences that are located in the promoter region of the genes that are activated by the hormone-receptor complex. As this enables the transcription of the according gene, these hormones are also called inductors of gene expression. The activation of gene transcription is much slower than signals that directly affect existing proteins. As a consequence, the effects of hormones that use nucleic receptors are usually long-term. Although the signal transduction via these soluble receptors involves only a few proteins, the details of gene regulation are yet not well understood. The nucleic receptors all have a similar, modular structure:

N-AAAABBBBCCCCDDDDEEEEFFFF-C

where CCCC is the DNA-binding domain that contains zinc fingers, and EEEE the ligand-binding domain. The latter is also responsible for dimerization of most nuclearic receptors prior to DNA binding. As a third function, it contains structural elements that are responsible for transactivation, used for communication with the translational apparatus. The zinc fingers in the DNA-binding domain stabilize DNA binding by holding contact to the phosphate backbone of the DNA. The DNA sequences that match the receptor are usually hexameric repeats, either normal, inverted or everted. The sequences are quite similar, but their orientation and distance are the parameters by which the DNA-binding domains of the receptors can tell them apart.

Steroid receptors

Steroid receptors are a subclass of nuclear receptors, located primarily within the cytosol. In the absence of steroid hormone, the receptors cling together in a complex called aporeceptor complex, which also contains chaperone proteins (also known as heatshock proteins or Hsps). The Hsps are necessary to activate the receptor by assisting the protein to fold in a way such that the signal sequence which enables its passage into the nucleus is accessible.
Steroid receptors can also have a repressive effect on gene expression, when their transactivation domain is hidden so it cannot activate transcription. Furthermore, steroid receptor activity can be enhanced by phosphorylation of serine residues at their N-terminal end, as a result of another signal transduction pathway, for example, a by a growth factor. This behaviour is called crosstalk.

RXR- and orphan-receptors

These nuclear receptors can be activated by:
- a classic endocrine-synthesized hormone that entered the cell by diffusion.
- a hormone that was built within the cell (for example, retinol) from a precursor or prohormone, which can be brought to the cell through the bloodstream.
- a hormone that was completely synthesized within the cell, for example, prostaglandin.

These receptors are located in the nucleus and are not accompanied by chaperone proteins. In the absence of hormone, they bind to their specific DNA sequence, repressing the gene. Upon activation by the hormone, they activate the transcription of the gene they were repressing.

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