Receptor cytoplasmic

The testes and adrenal glands produce 90% and 10%, respectively, of circulating testosterone. Testosterone enters prostate cells, where predominantly type II 5a-reductase activates testosterone to dihydrotestosterone, which combines with a cytoplasmic receptor. The complex enters the nucleus and induces changes in protein synthesis which promote glandular tissue growth of the prostate. Thus, 5a-reductase inhibitors (e.g., finasteride and dutas-teride) directly interfere with one of the major etiologic factors of BPH. 

Reproductive impairment was reported in several species of waterfowl from a marsh treated with 1.12 kg technical chlordane/ha (Table 13.4). Studies by Lundholm (1988) with two species of ducks (Anas spp.) and the domestic chicken (Gallus sp.) demonstrated that various organochlorine compounds, including chlordane, interfered (in a dose-dependent manner) with reproduction by reducing the binding of progesterone to its cytoplasmic receptor in the shell gland mucosa of birds, especially ducks. 

Ludke, J.L. 1977. DDE increases the toxicity of parathion to coturnix quail. Pest. Biochem. Physiol. 7 28-33. Lundholm, C.E. 1988. The effects of DDE, PCB and chlordane on the binding of progesterone to its cytoplasmic receptor in the eggshell gland mucosa of birds and the endometrium of mammalian uterus. Comp. Biochem. Physiol. 89C 361-368. 

Only 2% of total plasma testosterone is present in the active unbound state that penetrates the prostate cell, where it is converted to DHT by 5 a-reductase. DHT subsequently binds with a cytoplasmic receptor and is transported to the cell nucleus where transcription and translation of stored genetic material occur. 

The potential binding sites for various SH2 domain proteins on cytoplasmic receptor domains as well as on soluble proteins have been precisely mapped for several pTyr-containing target proteins. Apart from the impressive diversity of SH2 domain function, the fundamental property of all SH2 domains refers to the specific recognition of pTyr epitopes. 

Nudear hormone receptor one of a large class of cytoplasmic receptors that, when activated by binding to their ligands, migrate to the nucleus and act as transcription factors. 

All corticosteroids have the same general mechanism of action they traverse cell membranes and bind to a specific cytoplasmic receptor. The steroid-receptor complex translocates to the cell nucleus, where it attaches to nuclear binding sites and initiates synthesis of messenger ribonucleic acid (mRNA). The novel proteins that are formed may exert a variety of effects on cellular functions. The precise mechanisms whereby the corticosteroids exert their therapeutic benefit in asthma remain unclear, although the benefit is likely to be due to several actions rather than one specific action and is related to their ability to inhibit inflammatory processes. At the molecular level, corticosteroids regulate the transcription of a number of genes, including those for several cytokines. 

Some transmembrane receptors possess intrinsic tyrosine kinase activity. These receptors are known as receptor tyrosine kinases. Ligand binding to an extracellular domain of the receptor is coupled to the stimulation of tyrosine kinase activity localized on a cytoplasmic receptor domain. The ligand binding domain and the tyrosine kinase domain are part of one and the same protein. 

The effects of a chemical in a tissue frequently depend on the chemical s interaction with cell surface or cytoplasmic receptors. In some cases, a chemical interacts directly with the cell membrane and alters its permeability. The pharmacodynamic actions of drugs are usually mediated by interactions with a receptor, and a drug often competes with endogenous ligands of a receptor. The toxicity of environmental chemicals can also depend on and be mediated by interactions with receptors. In some cases, the responses are different for chemical exposures at different fetal stages of development, and it is possible to explain the different responses by the chronology of the development of fetal receptor systems. The fetus may develop receptor systems for a compound before it develops the ability to metabolize that compound thus, a low level of an active chemical can have greater and more persistent effects in the fetus than in the mother, whose metabolism limits the duration and extent of the effect. This is one mechanism for selective developmental toxicity of chemicals. 

All classes of steroid hormones bind to specific cytoplasmic receptors in their respective target tissues, and are then translocated to the nucleus. For example, testosterone, a lipid-soluble substance, enters the cell and is enzymatically reduced to dihydrotestosterone by 5-a reductase. Dihydrotestosterone then becomes bound to a specific androgen receptor site located in the cytoplasm. This complex becomes activated and is then translocated to the nucleus, where it binds to the chromatin acceptor site consisting of DNA and nonhistone chromosomal proteins. This interaction results in the transcription of a specific messenger RNA that is then relocated to the cytoplasm and translated on the cytoplasmic ribosomes, resulting in the synthesis of a new protein that sponsors the androgenic functions (Figure 61.6). 

Increased P450 synthesis requires enhanced transcription and translation. A cytoplasmic receptor (termed AhR) for polycyclic aromatic hydrocarbons (eg, benzo[a]pyrene, dioxin) has been identified, and the translocation of the inducer-receptor complex into the nucleus and subsequent activation of regulatory elements of genes have been documented. A pregnane X receptor (PXR), a member of the steroid-retinoid-thyroid hormone receptor family, has recently been shown to mediate CYP3 A induction by various chemicals (dexamethasone, rifampin) in the liver and intestinal mucosa. A similar receptor, the constitutive androstane receptor (CAR) has been identified for the phenobarbital class of inducers (Sueyoshi, 2001 Willson, 2002). 

Trioidothyronine from plasma, or that generated from T4 in the cells, may interact with specific cell receptors. However, there seems to be an equilibrium between the free and bound T3, and T3 penetrates the nuclear membrane without being bound to the cytoplasmic receptor protein. In the nucleus, however, T3 interacts with a chromatin-bound receptor and affects mRNA transcription. The responsiveness of various cells to T3 is correlated with the presence of nuclear T3 receptors. T3 receptors are also present in mitochondria 02 consumption by mitochondria is increased under the influence of T3. The function of cytosolic T3 receptors may be simply to concentrate T3 inside the cell rather than to serve as transporters. These processes are illustrated in Figure 16.15. 

Mechanism of action Spironolactone [spye row no LAK tone] is a synthetic aldosterone antagonist that competes with aldosterone for intracellular cytoplasmic receptor sites. The spironolactone-receptor complex is inactive, that is, it prevents translocation of the receptor complex into the nucleus of the target cell, and thus does not bind to DNA. This results in a failure to produce proteins that are normally synthesized in response to aldosterone. These mediator proteins normally stimulate the Na+-K+ exchange sites of the collecting tubule. Thus, a lack of mediator proteins prevents Na+ reabsorption and therefore K+ and H+ secretion. 

The adrenocorticoids bind to specific intracellular cytoplasmic receptors in target tissues. The receptor-hormone complex then translocates into the nucleus where it acts as a transcription factor to turn genes on or off, depending on the tissue. This mechanism requires time to produce an effect. There are other glucocorticoid effects, such as their requirement for catecholamine-mediated dilation of vascular and bronchial musculature or lipolysis, whose effects are immediate. The bases for these actions are unknown. 

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