ACTH Regulates the Function of the Adrenal Cortex

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The adrenal cortex produces the glucocorticoid hormones, cortisol and corticosterone, in the cells of its two inner zones, the zona fasciculata and the zona reticularis. These cells also synthesize androgens or male sex hormones, with the main androgen being dehydroepiandrosterone.

Glucocorticoids act on many processes, mainly by altering gene transcription and, thereby, changing the protein composition of their target cells. Glucocorticoids permit metabolic adaptations during fasting, which prevent the development of hypoglycemia or low blood glucose level. They also play an essential role in the body's response to physical and emotional stress. Other actions of glucocorticoids include their inhibitory effect on inflammation, their ability to suppress the immune system, and their regulation of vascular responsiveness to norepinephrine.

Aldosterone, the other physiologically important hormone made by the adrenal cortex, is produced by the cells of the outer zone of the cortex, the zona glomerulosa. It acts to stimulate sodium reabsorption by the kidneys.

Adrenocorticotropic hormone (ACTH) is the physiological regulator of the synthesis and secretion of gluco-corticoids by the zona fasciculata and zona reticularis. ACTH stimulates the synthesis of these steroid hormones and promotes the expression of the genes for various en zymes involved in steroidogenesis. It also maintains the size and functional integrity of the cells of the zona fascic-ulata and zona reticularis. ACTH is not an important regulator of aldosterone synthesis and secretion.

The actions of ACTH on glucocorticoid synthesis and secretion and details about the physiological effects of glucocorticoids are described in Chapter 34.

The Structure and Synthesis of ACTH. ACTH, the smallest of the six anterior pituitary hormones, consists of a single chain of 39 amino acids and has a molecular size of 4.5 kDa. ACTH is synthesized in corticotrophs as part of a larger 30-kDa prohormone called proopiomelanocortin (POMC). Enzymatic cleavage of POMC in the anterior pituitary results in ACTH, an amino terminal protein, and P-lipotropin (Fig. 32.4). P-Lipotropin has effects on lipid metabolism, but its physiological function in humans has not been estab-

Lph Cortisol

The proteolytic processing of proopiome lanocortin (POMC) by the human corti-cotroph. ß-LPH, ß-lipotropin.

lished. Although POMC can be cleaved into other peptides, such as P-endorphin, only ACTH and P-lipotropin are produced from POMC in the human corticotroph. Proteolytic processing of POMC occurs after it is packaged into secretory granules. Therefore, when the corticotroph receives a signal to secrete, ACTH and P-lipotropin are released into the bloodstream in a 1:1 molar ratio.

POMC is also synthesized by cells of the intermediate lobe of the pituitary gland and neurons in the hypothalamus. In the intermediate lobe, the ACTH sequence of POMC is cleaved to release a small peptide, a-melanocyte-stimulating hormone (a-MSH), and, therefore, very little ACTH is produced. a-MSH acts in lower vertebrates to produce temporary changes in skin color by causing the dispersion of melanin granules in pigment cells. As noted earlier, the adult human has only a vestigial intermediate lobe and does not produce and secrete significant amounts of a-MSH or other hormones derived from POMC. However, because ACTH contains the a-MSH amino acid sequence at its N-terminal end, it has melanocyte-stimulating activity when present in the blood at high concentrations. Humans who have high blood levels of ACTH, as a result of Addison's disease or an ACTH-secreting tumor are often hyperpigmented. In the hypothalamus, a-MSH is important in the regulation of feeding behavior.

CRH and ACTH Synthesis and Secretion. Corticotropin-releasing hormone is the main physiological regulator of ACTH secretion and synthesis. In humans, CRH consists of 41 amino acid residues in a single peptide chain.

CRH is synthesized in the paraventricular nuclei of the hypothalamus by a group of neurons with small cell bodies, called parvicellular neurons. The axons of parvicellular neurons terminate on capillary networks that give rise to hy-pophyseal portal vessels. Secretory granules containing CRH are stored in the axon terminals of these cells. Upon receiving the appropriate stimulus, these cells secrete CRH into the capillary network; CRH enters the hypophyseal portal circulation and is delivered to the anterior pituitary gland.

CRH binds to receptors on the plasma membranes of corticotrophs. These receptors are coupled to adenylyl cyclase by stimulatory G proteins. The binding of CRH to its receptor increases the activity of adenylyl cyclase, which catalyzes the formation of cAMP from ATP (Fig. 32.5). The rise in cAMP concentration in the corticotroph activates protein kinase A (PKA), which then phosphorylates cell proteins. PKA-mediated protein phosphorylation stimulates the corticotroph to secrete ACTH and P-lipotropin by unknown mechanisms.

Increased cAMP production in the corticotroph by CRH also stimulates expression of the gene for POMC, increasing the level of POMC mRNA in these cells (see Fig. 32.5). Thus, CRH not only stimulates ACTH secretion but also maintains the capacity of the corticotroph to synthesize the precursor for ACTH.

Glucocorticoids and ACTH Synthesis and Secretion. A

rise in glucocorticoid concentration in the blood resulting from the action of ACTH on the adrenal cortex inhibits the secretion of ACTH. Thus, glucocorticoids have a negativefeedback effect on ACTH secretion, which, in turn, re-

Corticotroph

P proteins

POMC mRNA

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Essentials of Human Physiology

Essentials of Human Physiology

This ebook provides an introductory explanation of the workings of the human body, with an effort to draw connections between the body systems and explain their interdependencies. A framework for the book is homeostasis and how the body maintains balance within each system. This is intended as a first introduction to physiology for a college-level course.

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