Protein hormone effect

Triiodothyronine (3, 5,3-L-triiodothyronine, T3) is a thyroid hormone. It is producedby outer ring deiodination of thyroxine (T4) in peripheral tissues. The biologic activity of T3 is 3-8 times higher than that of T4. T3 is 99.7% protein-bound and is effective in its free non-protein-bound form. The half-life of triiodothyronine is about 19 h. The daily tur nover of T3 is 75%. Triiodothyronine acts via nuclear receptor binding with subsequent induction of protein synthesis. Effects of thyroid hormones are apparent in almost all organ systems. They include effects on the basal metabolic rate and the metabolisms of proteins, lipids and carbohydrates. 

Figure 43-11. The hormone response transcription unit. The hormone response transcription unit is an assembly of DNA elements and bound proteins that interact, through protein-protein interactions, with a number of coactivator or corepressor molecules. An essential component is the hormone response element which binds the ligand (A)-bound receptor (R). Also Important are the accessory factor elements (AFEs) with bound transcription factors. More than two dozen of these accessory factors (AFs), which are often members of the nuclear receptor superfamily, have been linked to hormone effects on transcription. The AFs can interact with each other, with the liganded nuclear receptors, or with coregulators. These components communicate with the basal transcription complex through a coregulator complex that can consist of one or more members of the pi 60, corepressor, mediator-related, or CBP/p300 families (see Table 43-6).

A G-protein-mediated effect has an absolute requirement for GTP. Reference has already been made to the requirement for GTP in reconstituting hormone-stimulated adenylate cyclase activity. A similar requirement can be demonstrated when the effector is an ion channel, such as the cardiac atrial inward-rectifier K+ channel which is activated following stimulation of the M2 muscarinic acetylcholine receptor. Thus, in the experiment illustrated in Figure 7.8, the channel recorded with a cell-... 

Initially the level of insulin decreases, favouring increased rates of lipolysis, fatty acid oxidation, muscle protein degradation, glycogenolysis and gluconeogenesis. It soon increases, however, as a result of insulin resistance, when the stimulation of the above processes will depend on the cytokine levels. For details of endocrine hormone effects, see Chapter 12. For details of cytokines see Chapter 17. 

As discussed on p. 244, the hormone receptor does not interact directly with the RNA polymerase, but rather—along with other transcription factors—with a coactivator/me-diator complex that processes all of the signals and passes them on to the polymerase. In this way, hormonal effects lead within a period of minutes to hours to altered levels of mRNAs for key proteins in cellular processes ( cellular response ). 

The hormones of the pituitary gland participate in the control of reproductive function, body growth, and cellular metabolism deficiency or overproduction of these hormones disrupts this control. Clinical use of protein hormones in the past was limited because preparations had to come from glands or urine. The ability to prepare at least some of these hormones in large quantities by recombinant DNA techniques and the development of more stable analogues that can be injected in a depot form permit increased and more effective use of these hormones. 

Giampietro PG, Bruno G, Furcolo G et al. Soy protein formulas in children no hormonal effects in long term feeding. J. Pediatr. Endocrinol Metab. 17, 191-196, 2004. 

Norephedrine and ephedrine mimic and stimulate the release of the adrenal hormones norepinephrine and epinephrine. Norephinephrine raises heart rate and epinephrine stimulates carbohydrate metabolism resulting in an increased metabolic rate, fatty acids release from lipocytes (fat cells), and a protein sparing effect. Caffeine simply prolongs the effect. 

The G protein-GTP complexes related to receptors for these hormones activate adenylyl cyclase, which synthesizes the second messenger cAMP. Cyclic AMP activates protein kinases, which phosphorylate certain intracellular proteins (eg, enzymes), thus producing the hormonal effect. Conversely, dopamine binding to lactotroph receptors causes conformational changes in its G protein that reduce the activity of adenylyl cyclase and inhibit the secretion of prolactin. 

Hormones are secreted by specialized glands (adrenal, hypothalamus, ovary, pancreas, parathyroid, pineal, pituitary, testes, thyroid) or other tissues (e.g., heart, gut, and kidney), and regulate the cellular activities of distant tissues. Plasma levels of hormones are tightly regulated through homeostatic feedback systems. The peptide and protein hormones typically have short half-lives (minutes), which allow rapid changes in plasma levels and rapid enhancement or attenuation of their biological effects. 

Toro, M.J., E. Montoya, and L. Bimbaumer. 1987. Inhibitory regulation of adenylyl cyclases. Evidence inconsistent with beta gamma-complexes of Gi proteins mediating hormonal effects by interfering with activation of Gs. Mol. Endocrinol. 1 669-676. 

An important consideration to the pharmacologist is the useful lifetime of a drug in the body. Protein hormones have been modified chemically to lower their rate of removal from the bloodstream, prolong the effect of the injected hormone, and thus reduce the required frequency of administration. The modification of animal insulin by coupling to protamine-zinc is probably the best-known example. Others are the studies by Marshall on the possibility of lengthening the lifetime in the bloodstream of injected proteins by supplying them as dextran conjugates... 

As noted earlier, the velocity of any enzyme-catalyzed reaction is dependent upon the amount of effective enzyme present. Enzyme biosynthesis, like that of all proteins, is under genetic control, a long-term process. Biosynthesis of enzymes may be increased or decreased at the genome level. Various hormones can activate or repress the mechanisms controlling gene expression. Enzyme levels are the result of the balance between synthesis and degradation. This enzyme turnover may be altered by diverse physiological conditions, by hormone effects, and by the level of metabolites. 

Even though AMP, not cAMP, may be the protein kinase activator, glucagon causes its activation and insulin, inactivation. Details on such hormone effects are lacking. Also recall that malonyl-CoA inhibits palmitoyl-CoA-camitine acyltrans ferase, the rate-controlling enzyme in the /3-oxidation process. Thus, lipid oxidation is inhibited in an environment that favors lipid synthesis, as in the fed state, whereas lipid biosynthesis is inhibited in an environment favoring lipid oxidation, as in fasting. 

Receptors for protein hormones can be coupled to different transducing systems. Most of the data from studies approximately 10 years ago showed that many receptors are coupled to the adenylate cyclase system. However in the early 1980s it became clear that calcium fluxes and phospholipid turnover could also be important in conveying hormonal signals. During the last few years the number of papers describing the effects of hormones on phospholipid metabolism and calcium fluxes has increased tremendously and has outnumbered studies on cyclic AMP. 

The stimulation of steroid synthesis in gonadal cells is dependent on ongoing protein synthesis. Experiments with protein synthesis inhibitors have shown the presence of one or more proteins with half lives of 5-15 min which are essential for the expression of the stimulating hormone effect on steroidogenesis [42,45-47]. Many attempts to identify the protein(s) have been made but none have been detected that satisfy all the functional and kinetic criteria required. Using two-dimensional gel electrophoresis a 28 kDa protein has been identified recently [48], however its functional properties are unknown. It is also not known if the active protein is synthesised de novo or is derived from a precursor protein by covalent modification [49]. 

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