Hormone-receptor complex

FIGURE 15.21 Hormone (H) binding to its receptor (R) creates a hormone receptor complex (H R) that catalyzes GDP-GTP exchange on the o -subunit of the heterotrimer G protein (G ), replacing GDP with GTP. The G -subunit with GTP bound dissociates from the /37-subunits and binds to adenylyl cyclase (AC). AC becomes active upon association with G GTP and catalyzes the formation of cAMP from ATP. With time, the intrinsic GTPase activity of the G -subunit hydrolyzes the bound GTP, forming GDP this leads to dissociation of G GDP from AC, reassociation of G with the /Sy subunits, and cessation of AC activity. AC and the hormone receptor H are integral plasma membrane proteins G and G are membrane-anchored proteins. 

Steroid hormones act in a different manner from most hormones we have considered. In many cases, they do not bind to plasma membrane receptors, but rather pass easily across the plasma membrane. Steroids may bind directly to receptors in the nucleus or may bind to cytosolic steroid hormone receptors, which then enter the nucleus. In the nucleus, the hormone-receptor complex binds directly to specific nucleotide sequences in DNA, increasing transcription of DNA to RNA (Chapters 31 and 34). 

Coactivators enhancing the transcriptional activity of steroid hormone receptors activators include SRC-1 (steroid-receptor co-activator 1) or TEF2 (transcriptional intermediary factor 2), which are recruited by the DNA/ steroid hormone receptor complex. Their main role is to attract other transcriptional coactivators with histone acetyltransferase activity in order to decondense chromatin and allow for the binding of components of the general transcription apparatus. 

Pyridoxal phosphate is a coenzyme for many enzymes involved in amino acid metabolism, especially in transamination and decarboxylation. It is also the cofactor of glycogen phosphorylase, where the phosphate group is catalytically important. In addition, vitamin Bg is important in steroid hormone action where it removes the hormone-receptor complex from DNA binding, terminating the action of the hormones. In vitamin Bg deficiency, this results in increased sensitivity to the actions of low concentrations of estrogens, androgens, cortisol, and vitamin D. 

The dimer of the hormone-receptor complex should scrutinize an infinity of sequences before finding its FIRE. The role of the hormone in the recognition of the HRE seems to be that of dramatically increasing the velocity of DNA sequence recognition, that is to say, it binds and disconnects more quickly to sequences of nonspecific DNA. When it finds the sequence of its HRE, a bond of affinity is formed that is similar to that of hormone-receptor interaction (Kd in the nM range). 

The other transactivator domain, TAF2, is found immersed in the LBD and acts only when the hormone-receptor complex is formed. A sequence of 15 well-conserved amino acids from the different members of the family of nuclear receptors, and situated very close to the carboxyl end of the receptors, participates in it (Gruber et al. 2002 Nilsson et al. 2001). 

Second messengers often involved Protein kinases activated Hormone-receptor complex binds hormone response elements (HRE, of enhancer regions) inDNA... 

The action of a hormone is defined as the primary effect on a cell, usually the binding of the hormone to a specific receptor and the resultant interaction between the hormone-receptor complex and an effector system within the cell. The effect of a hormone is an experimental observation that is made either in vitro or in vivo it can be molecular, biochemical or physiological but, when a sufficient number of effects are established, a relationship between the action and effects can be drawn. This can best be described as a pyramid (Figure 12.2). The. function of a hormone is an... 

The action of a hormone is, first, binding to a receptor to form a hormone-receptor complex. The binding is reversible (i.e. equilibrium binding) as with other receptors. 

The hormone-receptor complex directly increases the activity of an enzyme, usually a protein kinase (Figure 12.4) or a phospholipase (Figure 12.5). 

Figure 12.8 Effector mechanism activation of a specific gene by hormone-receptor complex binding to DNA. A steroid is used to illustrate the mechanism. The hormone enters the cell and binds to its receptor (R) in the cytosol, the hormone-receptor complex enters the nucleus and binds to a specific sequence in the DNA that stimulates transcription of a gene or genes the resultant increase in mRNA increases the synthesis of specific proteins. The binding site on the DNA is specific and is usually termed a response element. Thyroxine (i.e. triiodothyronine) also uses this effector mechanism. Activation of genes, RNA processing to produce mRNA and translation are described in Chapter 20 (see Figures 20.20, 20.21 and 20.22).

The action of adrenaline (or noradrenaline) involves binding to an extracellular receptor, of which there are two classes, the a- and p-receptor. When the hormone binds to the P-receptor, the hormone-receptor complex activates adenyl cyclase, which catalyses the formation of cyclic AMP from ATP. 

In Uver, adrenaline binds to the a-receptor, and the hormone-receptor complex activates a membrane-bound phospholipase enzyme which hydrolyses the phospholipid phosphatidylinositol 4,5-bisphosphate. This produces two messengers, inositol trisphosphate (IP3) and diacylglycerol (DAG) (Figure 12.5). The increase in IP3 stimulates release of Ca ions from the endoplasmic reticulum into the cytosol, the effect of which is glycogen breakdown and release into the blood (see Figure 12.5 and Chapter 6). 

Factors that affect the formation of the hormone-receptor complex. 

These principles are similar to those that govern the relationship between an enzyme and its catalytic activity. For the hormone, R is equivalent to the enzyme, H to the substrate, and hormone-receptor complex to the enzyme-substrate complex. The activity of the substrate effector system is similar to the transition state. The cellnlar response to the hormone is similar to the catalytic role of the enzyme in the cell (Chapter 3),... 

An increase in the plasma concentration of the hormone increases its binding to the receptor in a hyperbolic manner so that, at a high concentration of hormone, the receptor approaches saturation with the hormone. However, in vivo, the number of receptors is much greater than required to bind all the hormone molecules so that, under physiological conditions, the binding sites never approach saturation with hormone. The concentration of the hormone-receptor complex, which governs the magnitude of the cellular response, can be increased by four factors. 

Figure 12.20 The G-protein activation/inactivation cycle. When the G-protein is associated with GTP, it is active when it is associated with GDP it is inactive. The hormone-receptor complex is the GTP exchange factor, which exchanges GDP for GTP to convert the inactive form to the active form. A GTPase activity inactivates the G-protein by hydrolysing GTP.

Figure 12.21 Effect of the hormone-receptor complex on activation of the G-protein and the resultant effect on the activation of adenyl cyclase. The hormone bind to the receptor to produce the hormone-receptor complex that activates to G-protein.

The illustration shows the particularly well-investigated mechanism of action for cortisol, which is unusual to the extent that the hormone-receptor complex already arises in the cytoplasm. The free receptor is present in the cytoplasm as a monomer in complex with the chaperone hsp90 (see p. 232). Binding of cortisol to the complex leads to an allosteric conformational change in the receptor, which is then released from the hsp90 and becomes capable of DNA binding as a result of dimerization. 

In the nucleus, the hormone-receptor complex binds to nucleotide sequences known as hormone response elements (HREs). These are short palindromic DNA segments that usually promote transcription as enhancer elements (see p. 244). The illustration shows the HRE for glucocorticoids (GRE ... 

The mechanism by which Na" is reabsorbed in coupled exchange with and K+ in the collecting duct has been discussed previously that is, Na+-driven K+ secretion is partially under mineralocorticoid control. Aldosterone and other compounds with mineralocorticoid activity bind to a specific mineralocorticoid receptor in the cytoplasm of late distal tubule cells and of principal cells of the collecting ducts. This hormone-receptor complex is transported to the cell nucleus, where it induces synthesis of multiple proteins that are collectively called aldosterone-induced proteins. The precise mechanisms by which these proteins enhance Na+ transport are incompletely understood. However, the net effect is to increase Na" entry across apical cell membranes and to increase basolateral membrane Na+-K+-ATPase activity and synthesis. 

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