Ep

FIGURE 11-6 Biosynthesis, packaging, and release of epinephrine in the adrenal medulla chromaffin cell. Abbreviations: PNMT, phenylethanolamine N-methyltransfer-ase; EP, epinephrine; NEP, norepinephrine; SAM, S-adenosylmethionine. Arrows pointing upward following the name of a compound refer to an increase in the concentration of that substance. Neurosecretory granules contain epinephrine, dopamine /3-hydroxylase, ATP, and Met- or Leu-enkephalin, as well as larger enkephalin-containing peptides or norepinephrine in place of epinephrine. Epinephrine and norepinephrine are contained in different cells. Enkephalins could also be contained in separate cells, although that is not completely clear. Presumably epinephrine, once secreted into the bloodstream, not only affects a-receptors of hepatocytes to ultimately increase blood glucose levels, as shown here, but also interacts with a-receptors on vascular smooth muscle cells and on pericytes to cause cellular contraction and increase blood pressure.

rate of decline following the removal of long-term stress. Denervation of the adrenal gland by severing the splanchnic nerve prevents elevations of tyrosine hydroxylase and dopamine ^-hydroxylase in stressed animals, whereas the activity of PNMT can still be induced by prolonged stress. Thus, nerve impulses, as indicated in Figure 11-6, are required for the stimulation of tyrosine hydroxylase and dopamine /^-hydroxylase. In repeated or long-term stress in which epinephrine is secreted from the adrenal medulla in appreciable amounts, there is an elevation of the capacity for further catecholamine synthesis. This is accomplished by increases in the enzymes of the biosynthetic pathway discussed earlier.

C. Content of Neurosecretory Granules and Secretion

The neurosecretory granules have been found to contain epinephrine, ATP, dopamine /^-hydroxylase, enkephalins, and enkephalin-containing peptides. The granules have an acidic interior, a condition that is known to stabilize epinephrine. The loss of dopamine /8-hydroxylase from chromaffin when the content of granules has been exhausted provides a rationale for the interval required to produce epinephrine again in high levels. This is related to the time involved in the resynthesis of dopamine /3-hydroxylase. The epinephrine released causes the contraction of the vascular system already discussed and leads to glycogen break down in the liver. Both of these processes probably proceed by the mediation of a-receptors.

Enkephalins exert an analgesic effect in the central nervous system. The fate of these polypeptide hormones released into the bloodstream from the adrenal medulla is not clear. Obviously, there could be some problem in transporting them into the brain in view of the blood-brain barrier, and they do not function there.

The release of enkephalins from the adrenal medulla secretory granule is proportional to the release of epinephrine. Enkephalin is stored in the granule together with epinephrine. Epinephrine, as indicated before, must enter the chromaffin granule after its conversion in the cytosol by PNMT. This uptake into the neurosecretory granule is stimulated by Mg2+ and ATP coupled to an H+ electrochemical gradient. The proton pumping Mg ATPase and an anion transport site apparently exist as parts of a macromolecular complex in the membrane of the chromaffin granule. The internal acidic milieu (pH 5.7) of the granule coincides with a pH optimum for dopamine /3-hydroxylase of pH 5.5 and explains the need for compartmentation of this enzyme.

Some new information on stimulators and inhibitors of catecholamine secretion is summarized in Table 11-1.

The chromaffin cells, maintained in cell culture conditions, are able to synthesize Met- and Leu-enkephalin de novo from radioactive amino acids. Reserpine (Figure 11-8), a drug that has catecholamine-depleting activity, causes nearly complete removal of catecholamines from the chromaffin cells, but the synthesis of enkephalins is enhanced under these conditions, particularly that of Met-enkephalin. The adrenal medulla usually contains Met-enkephalin at several times the level of Leu-enkephalin. Free enkephalin pentapep-tides are about 5% of the total enkephalin-containing peptides in the adrenal medulla.

The details of the mechanism of the intracellular events preceding exocytosis of the neurosecretory granules are unclear. Once again, Ca2+ (see Chapter 1) is involved and is elevated in the cytosolic compartment following the release of acetylcholine from the sympathetic autonomic cholinergic neuron and the postsynaptic binding of the transmitter to the chromaffin cell membrane receptor. The exocytotic event appears to be an all-or-none process in which the total contents of the granule are released into the extracellular space and into local blood circulation by entrance through fenestrated capillaries, which overcome diffusion barriers in the normal arteriolar wall. Even though epinephrine and enkephalins may be contained in the same chromaffin cell, there is evidence that their syn theses may be under different controls. The empty granule is probably reabsorbed by the chromaffin cell (see Chapter 4) or recycled from its fused state with the chromaffin membrane, because empty granules can be found in the medulla cells after secretion has occurred. During exocytosis, all of the products of the processing of proenkephalin are released, including the largest and even a small amount of proenkephalin itself. Three of the enkephalin-containing peptides are more active in isolated systems than the pentapeptides themselves, including peptide E, the heptapeptide, and the octapeptide. Peptide E is a 25-amino acid residue chain that contains one copy of Tyr-Gly-Gly-Phe-Met at the N-terminus and one copy of Tyr-Gly-Gly-Phe-Leu at the C-terminus. These may not be processed to free enkephalin. Enkephalin receptors are present in many tissues where these hormones may act, but it appears that they do not act in the brain. Some activities of enkephalins are reviewed in Table 11-2. Some of these actions may be in the realm of functions for the adrenal medulla enkephalins, although not much is known about how and where they act. It has been shown that Met-enkephalin changes membrane fluidity and modulates the production of nitric oxide and GMP in rat brain synaptosomes, and Met-enkephalin can potentiate immune reactivity when injected in low doses into the cerebral cavity. Both Met- and Leu-enkephalins appear to be agonists for the delta opioid receptor, and in cardiac myocytes Leu-enkephalin stimulates the levels of IP3 and intracellular Ca2+. The delta opioid receptor has been cloned, and a three-dimensional model of the ligand-bound receptor has been generated.

Prostaglandin E2 (PGE2) is bound specifically by particulate fractions of bovine, ovine, and human adrenal medulla cells. The binding is sensitive to treatment with phospholipases, glycosidases, trypsin, and sulf-hydryl reagents. The dissociation constant of 2 nM PGE2 indicates tight binding. The receptor site is quite specific for PGE2 compared to other prostaglandins, and prostacyclin (PGI2) has a lower affinity than PGE2. The prostaglandins bind to this receptor site in the same order that they demonstrate potency to release epinephrine from chromaffin granules. Thus, PGE may play a role in controlling the activity of adrenal medulla secretions.

D. Catabolism of Catecholamines

As with most other hormones, epinephrine is active at its receptor site in the unmetabolized form. The routes of metabolic inactivation have been well-established. These pathways of metabolism are shown

Dihydrobiopterin

Tetrahydrobiopterin

Dihydrobiopterin

Dihydrobiopterin reductase (regenerating enzyme)

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