Human Biochemistry, Volume 2 - Murray R. 1993

Biochemistry of Intracellular and Intercellular Communications
Pituitary and Hypothalamic Hormones
Anterior Pituitary Hormones - The Pro-opiomelanocortin (POMC) Peptide Family

This family consists of Peptides acting either as Hormones (adrenocorticotropin, lipotropin, melanocyte-stimulating hormone) or as Neurotransmitters or neuromodulators. Pro-opiomelanocortin (POMC) is synthesized as a precursor molecule consisting of approximately 285 amino acid residues and undergoes differential Processing in various Regions of the Pituitary Gland.

Distribution, Processing, and Functions of POMC Gene Products

The POMC gene is expressed in the anterior and intermediate lobes of the pituitary gland. The most evolutionarily conserved sequences, shared across different species, are localized in the N-terminal fragment encoding ACTH and β-endorphin. POMC or its related products are present in many other vertebrate Tissues, including the Brain, Placenta, gastrointestinal tract, reproductive tract, Lungs, and lymphocytes. This is primarily due to the expression of the POMC gene within these tissues rather than the uptake of gene products from the plasma; however, this mechanism can be considered proven only for the brain, placenta, and Testes. Related peptides have also been found in many invertebrate species.

The Processing of the POMC protein in the anterior and intermediate lobes of the pituitary proceeds differently. In adult humans, the intermediate lobe is rudimentary, but it is active in human fetuses, women in late Pregnancy, and many animal species. The processing of the POMC protein in peripheral tissues (intestine, placenta, male reproductive tract) is similar to that in the intermediate lobe of the pituitary. There are three main groups of peptides in the POMC family: 1) ACTH, from which melanocyte-stimulating hormone (α-MSH) and corticotropin-like intermediate lobe peptide can be derived; 2) β-lipotropin (β-LPH), which serves as a precursor for α-lipotropin, β-MSH, and β-endorphin, and consequently for α- and γ-endorphins; 3) the large N-terminal peptide, from which γ-MSH is formed. The Diversity of these products is due to the presence of multiple clusters of dibasic Amino Acids, which represent potential Cleavage sites for Trypsin-like Enzymes. Each of these peptides is preceded by Lys-Arg, Arg-Lys, Arg-Arg, or Lys-Lys residues. The prohormone segment is cleaved and undergoes post-translational modification via glycosylation, Acetylation, and phosphorylation. Subsequent cleavage of POMC products in the anterior and intermediate lobes of the pituitary occurs at the site between ACTH and β-LPH, leading to the Separation of the N-terminal peptide, including ACTH, from β-LPH (Fig. 45.7). ACTH_1-39 is then separated from the N-terminal peptide; further cleavages in the anterior pituitary practically do not occur. In the intermediate lobe, ACTH_1-39 is cleaved into α-MSH (residues 1–13) and corticotropin-like peptide (18–39); β-lipotropin (42–134) is converted into γ-lipotropin (42–101) and β-endorphin (104–134); β-MSH (84–101) is formed from γ-lipotropin.

The aforementioned peptides undergo numerous additional modifications. Most of the N-terminal peptide and ACTH_1-39 are present in the anterior pituitary in a glycosylated state, while α-MSH is found predominantly in the N-acetylated and C-terminally amidated form; deacetylated α-MSH is much less active. β-Endorphin in the intermediate lobe is rapidly acetylated; in contrast to α-MSH, acetylated β-endorphin exhibits 1,000-fold lower activity than the unmodified form. Thus, β-endorphin may exist in the pituitary in an inactive state. In the Hypothalamus, molecules of this peptide are not acetylated and apparently are present in the active form. β-Endorphin also undergoes C-terminal truncation to yield λ- and γ-endorphins (Fig. 45.7). These are the three main endorphins in the intermediate lobe of the rodent pituitary. The large N-terminal fragment probably also undergoes multiple cleavages, but less is known about its fate, although γ-MSH has been found in rat and bovine pituitaries. The structural data on these peptides were obtained mainly from studies on the rodent pituitary, but the General scheme of conversions appears to hold true for other species as well.

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Fig. 45.7. Cleavage products of pro-opiomelanocortin (POMC). MSH — melanocyte-stimulating hormone; CLIP — corticotropin-like intermediate lobe peptide; LPH — lipotropin.

The functions of most POMC family peptides have not been definitively established. The effects postulated for them are listed in Table 45.4.

Regulation of POMC Synthesis

POMC is synthesized by approximately 5% of the Cells in the anterior pituitary and by all cells in the intermediate lobe. The regulation of POMC Synthesis and Secretion in these pituitary regions differs markedly.

A. Anterior Lobe. Corticotropin-releasing hormone (CRH, corticoliberin) is the primary factor regulating POMC release from the anterior pituitary. It acts via a cAMP-mediated system that requires the presence of Ca²⁺. The stimulating effect of corticoliberin on POMC secretion is directly antagonized by glucocorticoid hormones. Glucocorticoids can also act on the hypothalamus by inhibiting corticoliberin synthesis, its secretion, or both processes. Adrenalectomy (which decreases glucocorticoid levels and increases CRH levels) is accompanied by a 20-fold increase in POMC gene METABOLISM/31.html">Transcription. Simultaneous administration of glucocorticoids can, however, attenuate this increase, with the suppressive action of glucocorticoids presumably mediated via specific receptors. The inhibition of ACTH secretion by glucocorticoids occurs more rapidly than their effect on POMC gene transcription, suggesting that these effects are mediated by independent mechanisms. Minor effects on POMC (ACTH) secretion by the anterior lobe include direct stimulation by vasopressin and α-adrenergic agents, indirect stimulation (via the Central Nervous system) by serotonin and acetylcholine, and inhibition by γ-aminobutyric acid (GABA). Dopamine has no effect on POMC secretion.

B. Intermediate Lobe. This pituitary lobe is poorly vascularized; the hypophyseal portal system does not reach it, and therefore it is not affected by corticoliberin. There are no glucocorticoid receptors in the intermediate lobe, which precludes the involvement of these hormones in regulating POMC production. The intermediate lobe of the pituitary is densely innervated by dopaminergic fibers and additionally contains serotonergic and catecholaminergic nerve terminals. Dopamine agonists (ergocryptine) decrease, whereas antagonists (haloperidol) increase, POMC mRNA levels and the secretion of POMC peptides. The timing and magnitude of these changes suggest coupling between Peptide Synthesis and secretion. These substances do not affect the anterior pituitary. POMC release in the intermediate lobe is stimulated by serotonin and β-adrenergic agents.

Table 45.4. Functions of POMC peptides

¹⁾ Established functions.

C. Other Tissues. Little is known about the regulation of POMC production in other tissues. It is unaffected by hypophysectomy, adrenalectomy, corticoliberin, or glucocorticoids. Chronic stress (immobilization) increases plasma ACTH levels and decreases pituitary ACTH content, yet POMC levels in the brain remain unchanged under these conditions. At the same time, acute stress leads to a decrease in β-endorphin content in the hypothalamus. The release of β-endorphin from the hypothalamus can be stimulated by estrogens.

Actions and Regulation of Specific Peptides

A. Adrenocorticotropic hormone (ACTH):

1. Structure and MECHANISM OF ACTION

ACTH is a single-chain polypeptide consisting of 39 amino acids (Fig. 45.8) that regulates the growth and function of the adrenal cortex. Full biological activity of the hormone requires the 24 N-terminal amino acids, which are identical across different species; the 16 C-terminal amino acids vary significantly.

A synthetic analogue of ACTH is widely used for diagnostic purposes.

ACTH enhances the synthesis and secretion of adrenal Steroids by promoting The conversion of Cholesterol to pregnenolone. This step involves The formation of a C₂₁ steroid from a C₂₇ steroid via the cleavage of a 6-carbon side chain. Because pregnenolone serves as the precursor for all adrenal steroids (see Fig. 48.3), prolonged ACTH stimulation leads to the overproduction of glucocorticoids, mineralocorticoids, and dehydroepiandrosterone (an androgen precursor). However, under physiological conditions, THE CONTRIBUTION OF ACTH to The production of the latter two classes of steroids is minimal. ACTH stimulates adrenal cortex growth (trophic effect) by enhancing Protein and RNA synthesis.

Like other Peptide Hormones, ACTH binds to Plasma Membrane Receptors. Within seconds of hormone-receptor interaction, a substantial increase in intracellular cAMP levels occurs. cAMP analogues mimic the effects of ACTH, and this effect is mediated via calcium.

ACTH activates adenylate cyclase in fat cells, resulting in cAMP-mediated lipase activation and enhanced lipolysis. Additionally, ACTH stimulates Insulin secretion by the Pancreas; however, these extra-adrenal effects are minor and require supraphysiological hormone concentrations.

2. Regulation

The formation of ACTH from the precursor protein POMC, as well as the Regulation of the synthesis and secretion of the latter, was discussed above. The primary regulation occurs via a negative feedback loop involving glucocorticoids and corticoliberin (CRH). Excessive amounts of ACTH can also inhibit CRH production through a "short-loop" mechanism. An important role in regulating the formation and secretion of ACTH belongs to the central nervous system. A number of neurotransmitters are involved in this type of regulation, including norepinephrine, serotonin, and acetylcholine. Most likely, it is neurotransmitters that mediate the stress response driven by ACTH, which stimulates the production of glucocorticoids necessary for adaptation to stimuli such as hypoglycemia, surgery, physical or emotional trauma, and the effects of cold and pyrogens.

Fig. 45.8. Structure of human ACTH.

3. Pathophysiology

Cushing's syndrome develops As a result of excess ACTH production by the pituitary gland or its ectopic production by a tumor. The mild MSH-like effect of ACTH, along with the secretion of ß- or a-MSH, leads to increased Skin pigmentation. The resulting Metabolic Disorders are caused by the hyperproduction of adrenal steroids and include: 1) a negative nitrogen, potassium, and phosphorus balance; 2) sodium retention, which can lead to Hypertension and edema; 3) impaired glucose tolerance or Diabetes Mellitus; 4) an increase in plasma Fatty acids; 5) a decrease in the number of blood eosinophils and lymphocytes coupled with an increase in polymorphonuclear leukocytes. Patients with Cushing's syndrome may exhibit muscle atrophy and a characteristic redistribution of fat with its accumulation on the trunk. A lack of ACTH associated with a tumor, infection, or pituitary infarction causes the opposite shifts.

B. ß-Lipotropin (ß-LPH). This peptide consists of the 91 amino acid residues of the C-terminal region of POMC (Fig. 45.7). ß-LPH contains the sequences of ß-MSH, y-lipotropin, Met-enkephalin, and ß-endorphin. ß-lipotropin, y-lipotropin, and ß-endorphin have been found in the human pituitary gland; ß-MSH was not detected. ß-Lipotropin is unique to the pituitary gland because in other tissues it is rapidly converted into y-lipotropin and ß-endorphin. ß-LPH contains a 7-Amino Acid Sequence (ß-LPH_47-53) identical to the ACTH_4-10 fragment (Fig. 45.9). ß-Lipotropin stimulates lipolysis and the mobilization of fatty acids, but its physiological role is minor. Apparently, it is significant only as a precursor to ß-endorphin.

C. Endorphins. ß-Endorphin represents the C-terminal segment of ß-lipotropin (the 31 amino acid residues from the C-terminus) (Fig. 45.7). The formation of a- and y-endorphins requires the cleavage of 15 or 14 amino acids, respectively, from the C-terminus of ß-endorphin. These peptides are found in the pituitary gland, where they exist in an acetylated form and are apparently inactive. Elsewhere (for example, in Neurons of the central nervous system), they are present in an unmodified form and therefore likely serve as neurotransmitters or neuromodulators. Endorphins bind to the same central nervous system receptors as morphine opiates and may play a role in the endogenous regulation of pain sensitivity. They exhibit a much higher activity (on a per-molecule basis, 18 to 30 times higher) than morphine. The enkephalin sequence is present in POMC, but it is not preceded by basic amino acids, and it apparently is neither cleaved nor expressed.

Fig. 45.9. Comparison of Amino acid sequences of ACTH and ß-lipotropin (ß-LPH) molecular fragments. Underlined residues indicate differences between the molecules. The ACTH molecule consists of 39 amino acids, while ß-lipotropin includes 91 amino acids.

D. Melanocyte-Stimulating Hormone (MSH).

MSH stimulates melanogenesis in certain species by causing the dispersion of intracellular melanin granules, which leads to skin darkening. Three different MSH molecules (a, ß, and y) are contained within the POMC molecule, and two of them (a and ß) are secreted in certain animal species. In humans, MSH activity is exhibited by Components of the larger y- or ß-lipotropin molecules. a-MSH contains an amino acid sequence identical to the ACTH_1-13 segment, but the N-terminal fragment of the molecule is in an acetylated form. a-MSH, as well as the corticotropin-like intermediate lobe peptide (CLIP), are typically found in animals with a well-developed intermediate pituitary lobe. These peptides have not been found in humans in the postnatal period.

Individuals with low glucocorticoid levels (Addison's disease) are characterized by heightened skin pigmentation associated with increased plasma MSH activity. This may be driven by ACTH secretion, but it is more likely the result of the combined secretion of ß- and y-lipotropins, which are known to possess MSH activity.