Harpers

THE DIVERSITY OF THE ENDOCRINE SYSTEM / 453POMC (1–134)ACTH (1–39)β-LPH (42–134)α-MSH(1–13)CLIP(18–39)γ-LPH(42–101)β-Endorphin(104–134)β-MSH(84–101)γ-Endorphin(104–118)α-Endorphin(104–117)Figure 42–15. Products of pro-opiomelanocortin (POMC) cleavage.(MSH, melanocyte-stimulating hormone; CLIP, corticotropin-like intermediatelobe peptide; LPH, lipotropin.)bles that in the intermediate lobe. There are three basicpeptide groups: (1) ACTH, which can give rise toα-MSH and corticotropin-like intermediate lobe peptide(CLIP); (2) β-lipotropin (β-LPH), which can yieldγ-LPH, β-MSH, and β-endorphin (and thus α- andγ-endorphins); and (3) a large amino terminal peptide,which generates γ-MSH. The diversity of these productsis due to the many dibasic amino acid clusters that arepotential cleavage sites for trypsin-like enzymes. Each ofthe peptides mentioned is preceded by Lys-Arg, Arg-Lys,Arg-Arg, or Lys-Lys residues. After the prehormone segmentis cleaved, the next cleavage, in both anterior andintermediate lobes, is between ACTH and β-LPH, resultingin an amino terminal peptide with ACTH and aβ-LPH segment (Figure 42–15). ACTH 1–39 is subsequentlycleaved from the amino terminal peptide, and inthe anterior lobe essentially no further cleavages occur. Inthe intermediate lobe, ACTH 1–39 is cleaved into α-MSH(residues 1–13) and CLIP (18–39); β-LPH (42–134) isconverted to γ-LPH (42–101) and β-endorphin (104–134). β-MSH (84–101) is derived from γ-LPH.There are extensive additional tissue-specific modificationsof these peptides that affect activity. Thesemodifications include phosphorylation, acetylation,glycosylation, and amidation.THERE IS VARIATION IN THE STORAGE& SECRETION OF HORMONESAs mentioned above, the steroid hormones and1,25(OH) 2 -D 3 are synthesized in their final activeform. They are also secreted as they are made, and thusthere is no intracellular reservoir of these hormones.The catecholamines, also synthesized in active form, arestored in granules in the chromaffin cells in the adrenalmedulla. In response to appropriate neural stimulation,these granules are released from the cell through exocytosis,and the catecholamines are released into the circulation.A several-hour reserve supply of catecholaminesexists in the chromaffin cells.Parathyroid hormone also exists in storage vesicles.As much as 80–90% of the proPTH synthesized is degradedbefore it enters this final storage compartment,especially when Ca 2+ levels are high in the parathyroidcell (see above). PTH is secreted when Ca 2+ is low inthe parathyroid cells, which contain a several-hour supplyof the hormone.The human pancreas secretes about 40–50 units of insulindaily, which represents about 15–20% of the hormonestored in the B cells. Insulin and the C-peptide (seeFigure 42–12) are normally secreted in equimolaramounts. Stimuli such as glucose, which provokes insulinsecretion, therefore trigger the processing of proinsulin toinsulin as an essential part of the secretory response.A several-week supply of T 3 and T 4 exists in the thyroglobulinthat is stored in colloid in the lumen of thethyroid follicles. These hormones can be released uponstimulation by TSH. This is the most exaggerated exampleof a prohormone, as a molecule containing approximately5000 amino acids must be first synthesized,then degraded, to supply a few molecules of theactive hormones T 4 and T 3 .The diversity in storage and secretion of hormonesis illustrated in Table 42–5.