A ring contacts

11 p substituted contact

FIGURE 10-27 Completed predicted structure of the GR HBD family, based on an alignment with thermitase, in crossed stereo. The original structure is in color, therefore some details are not obvious. Locations of contacts and point of entry of the steroid molecule are indicated by the current authors of HORMONES. The model is reproduced by permission from Goldstein, R. A., Katzenellenbogen, J. A., Luthey-Schulten, Z. A., Seielstad, D. A., and Wolynes, P. G. (1993). Three-dimensional model for the hormone binding domains of steroid receptors, Proc. Nat. Acad. Sci. USA 90, 9949-9953.

D-ring contacts

STEROID ENTRY A-ring first

FIGURE 10-27 Completed predicted structure of the GR HBD family, based on an alignment with thermitase, in crossed stereo. The original structure is in color, therefore some details are not obvious. Locations of contacts and point of entry of the steroid molecule are indicated by the current authors of HORMONES. The model is reproduced by permission from Goldstein, R. A., Katzenellenbogen, J. A., Luthey-Schulten, Z. A., Seielstad, D. A., and Wolynes, P. G. (1993). Three-dimensional model for the hormone binding domains of steroid receptors, Proc. Nat. Acad. Sci. USA 90, 9949-9953.

brain, the hypothalamus, the anterior pituitary (ACTH), and the zona fasciculata and zona reticularis of the adrenal cortex. The mineralocorticoid, aldosterone, is synthesized and secreted by cells of the outer layer of the adrenal cortex, the zona glomerulosa (Figure 10-4). The secretion of this hormone involves a set of signals different from those that we have introduced for Cortisol. Aldosterone is considered to be primarily a stress hormone where the signal would derive from norepinephrine release (Figure 10-7), which is a signal for the juxtaglomerular apparatus to start a cascade of events that culminates in the release of aldosterone (Chapter 15). Thus, stress-released norepinephrine would signal the macula densa of the juxtaglomerular apparatus of the kidney to release the enzyme renin into the bloodstream. Renin attaches to the N-terminus of a blood protein (Chapter 15) to commence an enzymatic cascade that generates angiotensin II and angiotensin III, which are hormones. Angiotensins II and III bind to a membrane receptor on cells of the adrenal zona glomerulosa. This effect, together with ACTH, which is also generated by stress through the humoral pathway (Figure 10-7), increases the synthesis and release of aldosterone. As this seems to be the key mechanism for the release of aldosterone, it is considered a

FIGURE 10-28 Speculative views of the binding of Cortisol by the glucocorticoid receptor and of aldosterone by the mineralocorticoid receptor.

stress hormone. This is in contrast to Cortisol, which is released during stress (ACTH) but is also released in a biorhythmic pattern under the control of serotonin. Serotonergic stimulation of Cortisol release, starting with CRH, is maximal during the morning hours and falls off beforehand and afterwards until the end of 24 hr, after which time the Cortisol level begins to increase again to reach an early morning high due to the activity of serotonergic neurons. Superimposed upon this pattern would be the release of Cortisol generating from stressful events. Aldosterone has salt conserving actions, specifically for Na+, which is reabsorbed by the Na+ conductance channel in lumenal epithelial cells such as in the gastrointestinal tract, sweat glands, submaxillary glands, etc. and therefore is a part of the system of water balance in the body. K+ is pumped out of cells in response to aldosterone. However, the

Major form of aldosterone binding to the mineralocorticoid receptor

Structure of the antagonist spironolactone

FIGURE 10-29 Potential structures of soluble aldosterone and structure of the antagonist, spironolactone.

FIGURE 10-28 Speculative views of the binding of Cortisol by the glucocorticoid receptor and of aldosterone by the mineralocorticoid receptor.

Structure of the antagonist spironolactone

FIGURE 10-29 Potential structures of soluble aldosterone and structure of the antagonist, spironolactone.

aldosterone-secreting system is not the only system controlling water balance. The topic of water homeostasis is covered in Chapter 15, where the mode of action of aldosterone is reviewed, and in Chapter 4, where the actions of vasopressin are presented.

B. Aldosterone-Producing System

This system is diagrammed in Figure 15-7. The initial signal is a fall in blood volume, a decrease in Na+ concentration in blood, a fall in blood pressure or release of catecholamines (stress) at the juxtaglomerular apparatus of the kidney, or the effect of angiotensin II. Any of these stimuli causes the release of renin, an enzyme with proteolytic activity, from juxtaglomerular cells. Renin acts on a plasma a2-globulin, releasing an N-terminal decapeptide by hydrolyzing, at a hydrophobic sequence (amino acids 10-13), a leucyl-leucyl peptide bond. The resulting decapeptide is angiotensin I, an intermediate with no hormonal activity. Angiotensin I is then attacked by a converting enzyme, which has a broad distribution in the vascular epithelium, lung, liver, adrenal cortex, pancreas, kidney, spleen, and neurohypophysis. This enzyme is a carboxypepti-dase that cleaves off the carboxy-terminal dipeptide, His-Leu, at a peptide bond connecting Phe and His. The resulting dipeptide is inactive and the octapeptide is angiotensin II, a hormone. This hormone has a short half-life of about 1 min because its activity is destroyed by angiotensinase, a Ca2+-activated enzyme found in the peripheral vascular beds. This hormone, in addition to its effects on zona glomerulosa cells of the adrenal cortex, sensitizes vascular smooth muscles to the contractile effects of norepinephrine. There are specific outer cell membrane receptors for angiotensin II in the zona glomerulosa of the adrenal cortex. Binding of the hormone to the receptor causes enhanced PI cycle turnover, with the activation of phosphatidylinositol protein kinase. In addition, ACTH binds to its receptor on these cells and elevates cAMP and PKA. Both pathways work in concert to stimulate aldosterone synthesis. Apppreciable levels of aldosterone are generated, primarily during stress.

TABLE 10-4 Effects of Overproduction of Cortisol (Cushing's Syndrome)"'6

Progesterone ch2oh

Cortisol

Progesterone

Cortisol

Testosterone

Testosterone

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