Receptors lipophilic hormones

To receive and pass on chemical or physical signals, cells are equipped with receptor proteins. Many of these are integral membrane proteins in the plasma membrane, where they receive signals from their surroundings. Other receptor proteins are located in intercellular membranes. The receptors for lipophilic hormones are among the few that function in a soluble form. They regulate gene transcription in the nucleus (see p. 378). 

Lipophilic hormones, which include steroid hormones, iodothyronines, and retinoic acid, are relatively small molecules (300-800 Da) that are poorly soluble in aqueous media. With the exception of the iodothyronines, they are not stored by hormone-forming cells, but are released immediately after being synthesized. During transport in the blood, they are bound to specific carriers. Via intracellular receptors, they mainly act on transcription (see p. 358). Other effects of steroid hormones—e.g., on the immune system—are not based on transcriptional control. Their details have not yet been explained. 

In the blood, there are a number of transport proteins for lipophilic hormones (see p. 276). Only the free hormone is able to penetrate the membrane and enter the cell. The hormone encounters its receptor in the nucleus (and sometimes also in the cytoplasm). 

The receptors for lipophilic hormones are rare proteins. They occur in small numbers (10 -10" molecules per cell) and show marked specificity and high affinity for the hormone M). After binding... 

Receptors for lipophilic hormones mediate the effects of steroid hormones and related signaling substances. They regulate the transcription of specific genes (see p. 378). The products of several oncogenes (e.g., erbA) belong to this superfamily of ligand-controlled transcription factors. 

Signal transduction by nuclear receptors is shown schematically in fig. 4.4. The natural hgands of nuclear receptors are lipophilic hormones that can enter the cell in a passive manner. A transmittance of the signal at the cell membrane, is not necessary, as is the case in the signaling via transmembrane receptors. Once inside the cell the hormone... 

Hormones Some lipophilic hormones (e.g. the steroid hormones, thyroxine, retinoic acid and vitamin D) diffuse across the plasma membrane and interact with intracellular receptors in the cytosol or nucleus. Other lipophilic hormones (e.g. the prostaglandins) and hydrophilic hormones (e.g. the peptide hormones insulin and glucagon and the biogenic amines epinephrine and histamine) bind to receptor proteins in the plasma membrane. 

Small lipophilic (lipid-soluble) hormones diffuse across the plasma membrane and then interact with intracellular receptors in the cytosol or nucleus. The resulting hormone-receptor complex often binds to regions of the DNA and affects the transcription of certain genes (see Topic G7). Small lipophilic hormones with intracellular receptors include the steroid hormones which are synthesized from cholesterol (see Topic K5) (e.g. the female sex hormones estrogen and progesterone), thyroxine which is produced by thyroid cells and is the principal iodinated compound in animals, retinoic acid which is derived from vitamin A, and vitamin D which is synthesized in the skin in response to sunlight (see Topic K5). 

Lipophilic hormones with cell-surface receptors... 

Enzyme receptors are transmembrane receptors with intrinsic enzymatic activity. Examples are the receptor tyrosine kinases (RTKs), which autophosphorylate their own tyrosine residues, such as the growth factor receptors and the insulin receptor. And, finally, there are the intracellular DNA sinding receptors. They bind lipophilic ligands that pass through the membrane. They address genes directly. Examples are the steroid hormone receptors (see Chapter 11). (This figure was donated by Professor Martin Lohse, University of Wurzburg.)... 

In the next chapter, we shall see how signal-responsive transcription factors control gene transcription. Moreover, we shall see in Chapter 11 that lipophilic hormones, such as steroid hormones and retinoids, use a more direct route to the gene, because these hormones bind to diffusible cytosolic receptors that are also transcriptional activators. 

Nuclear receptors. Intracellular DNA-binding proteins which bind lipophilic ligands which pass the membrane without assistance. Examples are the steroid hormone receptors and the receptors for non-steroidal ligands, such as retinoids and the hormone thyroxin. 

Polychlorinated diphenyl ethers (PCDE) are common impurities in chlorophenol formulations, which were earlier used as fungicides, slimicides, and as wood preservatives. PCDEs are structurally and by physical properties similar to polychlorinated biphenyls (PCB). They have low water solubility and are lipophilic. PCDEs are quite resistant to degradation and are persistent in the environment. In the aquatic environment, PCDEs bioaccumulate. These compounds are found in sediment, mussel, fish, bird, and seal. PCDEs show biomagnification potential, since levels of PCDEs increase in species at higher trophic levels. PCDEs are also detected in human tissue. Despite the persistence and bio accumulation, the significance of PCDEs as environmental contaminants is uncertain. The acute toxicity and Ah-receptor-me-diated (aryl hydrocarbon) activity of PCDEs is low compared to those of polychlorinated di-benzo-p-dioxins (PCDD) and dibenzofurans (PCDF). Due to structural similarity to thyroid hormone, PCDEs could bind to thyroid hormone receptor and alter thyroid function. Furthermore, PCDEs might be metabolized to toxic metabolites. In the environment, it is possible that photolysis converts PCDEs to toxic PCDDs and PCDFs. 

Nuclear hormone receptors comprise a gene superfamily encoding for transcription factors that transfer endogenous (e.g., small, lipophilic hormones)... 

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