Cytosolic receptors

Sirolimus (SRL), also termed rapamycin is a macrolide lactone isolated from the ascomycete species Stre-ptomyces hygroscopicus. After binding to its cytosolic receptor FKBP-12 the resulting complex inhibits the multifunctional serine-threonine kinase mTOR (mammalian target of rapamycin). Inhibition of mTOR prevents activation of the p70S6 kinase and successive... 

Cyclosporine A (CsA) is a water-insoluble cyclic peptide from a fungus composed of 11 amino acids. CsA binds to its cytosolic receptor cyclophilin. The CsA/cyclophilin complex reduces the activity of the protein phosphatase calcineurin. Inhibition of this enzyme activity interrupts antigen receptor-induced activation and translocation of the transcription factor NEAT to the nucleus which is essential for the induction of cytokine synthesis in T-lymphocytes. 

Tacrolimus (TRL), in the past also named FK506, belongs to the group of macrolides and is produced by a special actinomycete species. TRL binds to its cytosolic receptor FKBP-12, however, it also blocks calcineurin activity and subsequently cytokine synthesis. 

Laboratory studies have reported an excellent correlation between the toxicities of the dibenzo-p-dioxins and related compounds and their abilities to induce aryl hydrocarbon hydroxylase (AHH) activity (Poland and Knutson 1982), suggesting that some mechanistic features may be common to both the toxic and AHH-inducing activities of these compounds. Indeed, both the toxicities and the AHH-inducing activities of the dibenzo-p-diox-ins have found to correlate well with binding affinities to a cytosolic receptor (Poland, Greenlee, and Kende 1979 Poland and Knutson 1982). 

McKinney, J. D., G. A. Long, and L. G. Pederson. 1984. QSAR and Dioxin Binding to Cytosol Receptors A Theoretical Model Based on Molecular Parameters. Quant. Struct.-Act. Relat. 3, 99. 

The initial step after cellular uptake of T4 is metabolic transformation to 3,5,3, -tri-iodothyronine (T3) (Fig. 52-8), which interacts with cytosolic and nuclear receptors, as well as with synaptosomal membrane binding sites of unknown function [25], Cytosolic receptors are proteins of 70 kDa that do not appear to undergo translocation to cell nuclei, nor do they appear to be nuclear proteins that have leaked out of cell nuclei during cell rupture nuclear receptors are proteins of 50 70 kDa that have both DNA-and hormone-binding domains [25,26,28],... 

Group I planar PCBs are 10 times more toxic and 100 times more effective as inducers of cytochrome P-450c-dependent monooxygenase and 70 times more effective in competitively displacing 2,3,7,8-TCDD from a rat cytosol receptor protein than Group II planar PCBs (Table 24.4 ... 

Receptor-effector mechanisms include (1) enzymes with catalytic activities, (2) ion channels that gate the transmembrane flux of ions (ionotropic receptors), (3) G protein-coupled receptors that activate intracellular messengers (metabotropic receptors), and (4) cytosolic receptors that regulate gene transcription. Cytosolic receptors are a specific mechanism of many steroid and thyroid hormones. The ionotropic and metabotropic receptors are discussed in relevance to specific neurotransmitters in chapter 2. 

Here are some insights into how l,25(OH)2D works. Like steroid hormones and retinoic acid, l,25(OH)2D binds to and activates a cytosolic receptor present in most cells of the human body. The activated receptor migrates to the cell nucleus, binds to a specific nucleotide sequence in the nuclear DNA, and acts as a transcription factor. Directly or indirectly, the expression of some 200 genes is affected as a result. 

Androgens and estrogens are, respectively, male and female sex hormones. They act through cytosolic receptors that, when activated, migrate to the nucleus and influence gene expression. 

Antiandrogens such as cyproterone acetate (5.54) or the nonsteroidal flutamide (5.55, a substituted anilide) are competitive antagonists on the cytosol receptor. They do not prevent DHT formation rather, they inhibit the nuclear retention of DHT in the prostate. They cause feminization in male fetuses and decrease libido in males. Cyproterone is also an active progestogen. In men, antiandrogens are used commonly in the treatment of prostatic cancer and uncommonly to inhibit sex drive in hypersexuality in women, antiandrogens are used to treat virilization. Bicalutamide (5.56) and nilutamide (5.57) are potent, orally active antiandrogens that may be used in the treatment of metastatic prostate carcinoma. 

The steroid hormones are distributed throughout the entire organism by means of the circulatory system. Transport often occurs in the form of a complex with a specific binding protein. An example for such a binding protein is transcortin, which is responsible for the transport of the corticosteroids. The steroid hormones enter the cell by diffusion and activate the cytosolic receptors. 

The polycyclic type of inducer has been the most successfully studied, and this work led to the discovery that a cytosolic receptor was involved in induction by polycyclic hydrocarbons. The receptor, AhR, is found in many different cell types. 

This stage involves alteration in gene expression and regulation via cell surface or cytosolic receptors. Most promoters affect gene expression via perturbation of the signal transduction pathways tyrosine kinase, steroid, or G protein linked. The result is cell proliferation. 

Nitric oxide Nitric oxide From arginine + 02 Cytosolic receptor (guanylate cyclase) and... 

Effect of vitamin D on the intestine 1,25-diOH D3 stimulates intestinal absorption of calcium and phosphate. 1,25-diOH D3 enters the intestinal cell and binds to a cytosolic receptor. The 1,25-diOH D3-receptor complex then moves to the nucleus where it selectively interacts with the cellular DNA. As a result, calcium uptake is enhanced by an increased synthesis of a specific calcium-binding protein. Thus, the mechanism of action of 1,25-diOH D3 is typical of steroid hormones (see p. 238). 

Sirolimus binds to the cytosolic protein FK-binding protein R (FKBP-12) but does not block calcineurin activity. It does not bind to cyclophilins, which are cytosolic receptors for cyclosporine. Unlike cyclosporine and tacrolimus, sirolimus does not inhibit the activation of NFAT responsive genes. After binding to its cytosolic receptors, sirolimus inhibits a protein kinase, the mammalian target of rapamycin (mTOR) pathway, via suppression of PP2-A. When mTOR is inhibited, the cells will not proceed to the S phase, and the cell cycle will be blocked (Fig. 4.3). As a result, sirolimus blocks T-cell proliferation but its effects are downstream of the IL-2 receptors. IL-2 binding to its receptors activates intracellular protein kinases that in turn activate gene transcription and T-cell proliferation. 

FIGURE 28-2 Primary cellular locations of hormone receptors. Peptide hormones tend to bind to surface membrane receptors (site 0 steroid hormones bind to cytosolic receptors [site 10 and thyroid hormones bind to receptors in the cell nucleus [site III). 

Nuclear Hormone Receptors. Certain hormones interact directly with hormonal receptors that are located on the chromatin within the cell nucleus (see Fig. 28-2).3 Thyroid hormones (T3 and T4) are a primary example of hormones that bind directly to nuclear receptors.29 After binding, thyroid hormones invoke a series of changes similar to those caused by the steroid-cytosolic receptor complex that is, the nucleus begins to transcribe messenger RNA, which is ultimately translated into specific proteins. In the case of the thyroid hormones, these new proteins usually alter the cell s metabolism. Thyroid hormones are discussed in more detail in Chapter 31. 

FIGURE 29-5 Effect of aldosterone on renal tubule cells. CO Aldosterone CAD enters the cell and binds to a cytosolic receptor CR], creating an activated hormone-receptor complex CA-R],... 

TCDD, which is substituted in all four lateral positions. Addition of one, two, or four nonlateral chlorine substituents, or removal of lateral chlorine substituents, resulted in congeners with lower binding affinities. The stereospecific nature of the binding suggested the existence of a cytosolic receptor as a mediator in responses caused by 2,3,7,8-TCDD and related compounds. 

Denomme MA, Homonoko K, Fujita T, et al. 1985. Effects of substituents on the cytosolic receptor-binding affinities of aryl hydrocarbon hydroxylase induction potencies of 7-substituted 2,3-dichlorodibenzo-p-dioxins. Mol Pharmacol 27 656-661. 

Gasiewicz TA, Rucci G. 1984. Cytosolic receptor for 2,3,7,8-tetrachlorodibenzo-p-dioxin. Evidence for a homologous nature among various mammalian species. Mol Pharmacol 26 90-98. 

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