Growth Hormone

A. Growth Hormone Structure

The sequence of human GH is given in Figure 5-3. Human GH is a peptide containing two disulfide bonds with a molecular weight of 22,000, although a smaller variant of 20,000 accounts for about 10% of GH and lacks amino acids 32-46 through processing of the GH mRNA precursor. A large form of GH is represented by a dimer stabilized by an interchain disulfide bond, and larger forms have been described. The forms larger than 22,000 probably are not physiologically important. A glycosylated form of GH is produced by the placenta that is 25,000. As mentioned previously, GH is related to chorionic somatomammotropin (CS) produced by the human placenta. hCS contains 191 amino acids and is quite similar to hGH. CS could have arisen by a new duplication of the primate GH gene or

FIGURE 5-17 Signal transduction mechanisms involved in prolactin (PRL) regulation. Abbreviations: (in nucleus) ER, estrogen receptor; TR, thyroid hormone receptor; GR, glucocorticoid receptor; (in cytoplasm) ER, endoplasmic reticulum. Reproduced with permission from Molitch, M. E. (1995). Prolactin. In "The Pituitary" (S. Melmed, ed.), pp. 136-186. Blackwell Science, Oxford.

FIGURE 5-17 Signal transduction mechanisms involved in prolactin (PRL) regulation. Abbreviations: (in nucleus) ER, estrogen receptor; TR, thyroid hormone receptor; GR, glucocorticoid receptor; (in cytoplasm) ER, endoplasmic reticulum. Reproduced with permission from Molitch, M. E. (1995). Prolactin. In "The Pituitary" (S. Melmed, ed.), pp. 136-186. Blackwell Science, Oxford.

extensive interchange of the GH gene with the CS gene. hCS has 0.1% of the growth-promoting activity of hGH. Earlier comparisons were made between the GH-CS gene family and PRL. The gene for hGH is pictured diagrammatically in Figure 5-20.

The gene cluster that gives rise to GH-1, GH-2, CS-1, CS-2, and CS-P is shown in Figure 5-21. The gene cluster consists of five genes, with the gene for GH-1 at the 5' end. GH-1 or GH-N is the somatotrophic cell pituitary hormone, followed by CS-P, CS-1, GH-2, and CS-2. There is at least 90% base sequence homology among the genes. A 217-amino-acid prehormone is cleaved to yield the mature 191 amino acid hormone with a 22,000 molecular weight. The GH-1 or GH-N gene gives rise to two forms, as shown in Figure 5-20. The two proteins are similar, except that the 20,000

h2n 0

ch2chc0ch3 c0nhch2ch2n(c2h5)2

,och3

ci nh2

p-Chlorophenylalanine Metoclopramide

(4-amino-5-chloro-N-[(2-die thy laminóle thy 1]-2-methoxybenzamide)

FIGURE 5-18 Structures of inhibitors of serotonin biosynthesis.

TABLE 5-3 Substances Affecting Prolactin Release*

Stimulatory

Inhibitory

Thyrotropin-releasing hormone Vasoactive intestinal polypeptide Peptide histidine isoleucine Serotonin Opioid peptides Growth hormone-releasing hormone Gonadotropin-releasing hormone Oxytocin Vasopressin Histamine (Hi) Bradykinin Angiotensin II Neurotensin Substance P Cholecystokinin Bombesin Secretin Gastrin Galanin Calcitonin

Calcitonin gene-related peptide Thymosin Factor 5 Melatonin

Other posterior pituitary factors (?) Platelet-activating factor Epidermal growth factor a-Melanocyte-stimulating hormone

Dopamine

Gonadotropin-associated peptide y-Aminobutyric acid Somatostatin

Acetylcholine

" Reproduced with permission from Molitch, M. E. (1995). Prolactin. In "The Pituitary" (S. Melmed, ed.), pp. 136-186. Blackwell Science, Oxford.

form does not express early antilipolytic activity. The lactogenic activity of CS is similar to that of GH and PRL, but its affinity for the GH receptor is one ten-thousandth that of GH.

One gram of somatotropic tissue can produce 2

6 mg of GH-1 (22 kDa) per day. There is also a high level of expression of CS-1 and CS-2 in placenta.

The hGH gene promoter region 500 bp upstream of the transcriptional start is shown in Figure 5-22. Nuclear factors binding to this region are NF-1, USF, AP2, and the glucocorticoid receptor. Pit-1 (GHF-1) is very active, as discussed previously. A silencer is located 200 bp farther upstream, and these sequences will silence pituitary cell expression but not that of placental cells. The protein binding to this region is called pituitary-specific factor 1 (PSF-1), but this factor is absent from placental cells. PSF-1 may interact with Pit-1. Pit-1 contains helix-turn-helix motifs, and the helices are thought to contact the major groove of target DNA and form DNA-dependent homodimers.

Children with no expression of GH-1 have pronounced defective growth patterns. Some of these children raise antibodies against GH when they are treated due to the absence of GH from their systems, although antibody levels seem lower with the use of highly purified biosynthetic human GH preparations than with pituitary extract. Other genes in the GH-CS gene cluster appear to be functional but they do not replace the absence of GH-1. This syndrome seems to entail a loss of 6.7 kb of DNA between two HindUl sites normally containing the GH-1 gene. There are several modes of GH-1 gene deletion in this disease, involving unequal recombination and crossing over at meiosis. There is evidence for several independent recombination events. PCR analysis helps to sort out the nature of the deletion, but this approach also has some deficiencies.

B. Regulation of Growth Hormone Secretion

The overall regulation of GH secretion and its actions are summarized in Figure 5-23 and Table 5-3. At the hypothalamic level a number of aminergic neurons can exert influences on GH secretion. These neurons are reviewed generally in Chapter 3. Figure 5-23 shows catecholaminergic neurons, which may stimulate the release of GRH from its neuron, and serotonergic as well as /3-endorphinergic neurons, which could stimulate the release of TRH from its nerve ending. Although less certain, melatoninergic neurons or melatonin from the pineal gland could stimulate the release of somatostatin from somatostatinergic neurons, which inhibit the release of GH from the somatotroph. These interne-urons are probably linked to various conditions known to operate through the CNS: hypoglycemia (insulin?), exercise, and surgical stress. Once released from the somatotroph, GH circulates in the blood at levels greater than 3 ng/ml, with a total daily output of 1-4 mg.

GH has several major activities. It interacts with GH receptors in adipose cells and brings about an increase in free fatty acids by increasing lipolysis. Phosphorylation of triglyceride lipase possibly is involved in this mechanism. GH interacts with receptors on the cell membranes of liver, kidney, and muscle and causes the release of somatomedins (IGFs) into circulation. Somatomedins are mitogenic (growth stimulatory) for many types of somatic cells and are of great importance in growth. GH also interacts with vascular walls, re-

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