Biochemistry

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Tryptophan is the precursor of melatonin. After uptake from the extracellular blood vascular system, this amino acid is converted, in the pinealocyte, to 5-hydroxytryptophan catalyzed by tryptophan hydroxylase. Serotonin is the product of the next step in the pathway achieved by the action of aromatic l-amino acid decarboxylase on 5-hydroxytryptophan.

Serotonin is the trivial name for 5-hydroxytrypta-mine. The serotonin concentration remains high in the pineal during daylight hours as a result of the signaling mechanism reviewed in Figure 18-8, but falls in darkness when serotonin either is converted to melatonin or falls in concentration for some other reason. Two enzymes achieve this conversion: serotonin N-acetyl-transferase, which converts serotonin, using acetyl-coenzyme A, to N-acetylserotonin, and hydroxyindole-O-methyltransferase (HIOMT), which catalyzes the transfer of a methyl group from S-adenosylmethionine (SAM) to the 5-hydroxyl of N-acetylserotonin. The product of this last reaction is melatonin (5-methoxy-N-acetyltryptamine). During darkness, there is increased release of norepinephrine from the sympathetic neurons terminating on the pinealocytes (Figure 18-6).

Melatonin circulates in the blood and is metabolized by the liver. Apparently, some or all of the melatonin is secreted either into the blood directly or into the cerebrospinal fluid before entering the bloodstream. It is unclear exactly how the metabolism of melatonin is partitioned between the liver and central nervous system, if the latter plays a role in this activity at all. Various effects of melatonin have been ascribed to occur in the central nervous system and perhaps elsewhere.

The biosynthesis of melatonin is shown in Figure 18-7. In darkness, norepinephrine is secreted from adrenergic neurons ending on pinealocytes. The norepinephrine binds to the ^-adrenergic receptor (see Chap figure 18-5 Anatomy of the pineal organ with respect to light stimulus. Light is transmitted from the retina along several brain pathways, which merge at the superior cervical ganglia of the sympathetic nervous system, as do all neural impulses of central nervous system origin that travel to the pineal. These impulses affect the synthesis of melatonin through the mediation of norepinephrine release and its stimulation of ¡3-adrenergic receptors on the pineal cell membranes. This conversion of neural input identified the pineal as a neuroendocrine transducer. Reproduced from Wurtman, R. J. (1980). "Neuro-endocrinology," (D. T. Krieger and J. C. Hughes, eds.), p. 103. Sinauer Associates, Sunderland, MA. courtesy of Nancy Lou (Gahan) Makris.

figure 18-5 Anatomy of the pineal organ with respect to light stimulus. Light is transmitted from the retina along several brain pathways, which merge at the superior cervical ganglia of the sympathetic nervous system, as do all neural impulses of central nervous system origin that travel to the pineal. These impulses affect the synthesis of melatonin through the mediation of norepinephrine release and its stimulation of ¡3-adrenergic receptors on the pineal cell membranes. This conversion of neural input identified the pineal as a neuroendocrine transducer. Reproduced from Wurtman, R. J. (1980). "Neuro-endocrinology," (D. T. Krieger and J. C. Hughes, eds.), p. 103. Sinauer Associates, Sunderland, MA. courtesy of Nancy Lou (Gahan) Makris.

ter 11) on the pinealocyte membrane (may be a synapse) and results in the stimulation of intracellular cyclic AMP levels. The elevation of cyclic AMP probably operates as described elsewhere (Figure 1-37) and stimulates protein kinase activity, which in turn causes the phosphorylation of specific proteins and results in the stimulation of the synthesis of N-acetyltransferase.

In cultured rat pineal glands during the induction of serotonin-N-acetyltransferase by catecholamine, a nuclear protein is phosphorylated in the early stages of enzyme induction. This protein is also phosphorylated when the glands are treated directly with dibutyryl cyclic AMP, overstepping catecholamine ligand and its receptor. Increased levels of this enzyme lead to the conversion of serotonin to melatonin and its secretion from the cell probably into the bloodstream. Environmental light, perceived via the retinas, diminishes the flow of impulses along the pineal's sympathetic nerves, thus decreasing the release of norepinephrine onto pi-nealocytes. This decreases the activities of serotonin-N-acetyltransferase and HIOMT, suppressing the synthesis and secretion of melatonin. This pineal mech

FIGURE 18-6 Neural connections between the eyes and the pineal gland as demonstrated in various mammals and synthesis of melatonin within the pineal gland. Abbreviations: HIOMT, hydroxyindole-O-methyltransferase; NAT, N-acetyltransferase; NE, norepinephrine, PVN, paraventricular nucleus; SCG, superior cervical ganglia; SCN suprachiasmatic nucleii. Reproduced with permission from Shafii, M., and Shafii, S. L. (eds.) (1990). "Biological Rhythms, Mood Disorders, Light Therapy, and the Pineal Gland." American Psychiatric Press, Inc., Washington, DC.

FIGURE 18-6 Neural connections between the eyes and the pineal gland as demonstrated in various mammals and synthesis of melatonin within the pineal gland. Abbreviations: HIOMT, hydroxyindole-O-methyltransferase; NAT, N-acetyltransferase; NE, norepinephrine, PVN, paraventricular nucleus; SCG, superior cervical ganglia; SCN suprachiasmatic nucleii. Reproduced with permission from Shafii, M., and Shafii, S. L. (eds.) (1990). "Biological Rhythms, Mood Disorders, Light Therapy, and the Pineal Gland." American Psychiatric Press, Inc., Washington, DC.

anism may mediate the stimulation of ovarian growth that occurs when young rats are placed under constant light.

The metabolic reactions involved in the conversion of tryptophan to melatonin are shown in Figure 18-7. The regulation of N-acetyltransferase is more elaborate than has been described up to this point. As mentioned before, the increased elaboration of norepinephrine, stimulated by the absence of light, results in the enhanced synthesis of N-acetyltransferase and coenzyme A. An N-acetyltransferase-inactivating substance (NIS) may be present. The NIS presumably would act when the concentration of acetyl-CoA falls (light) to further reduce the production of melatonin. •y-Aminobutyric acid (GABA) could have a modulating effect on norepinephrine increases in N-acetyltransferase protein. Cyclic GMP may have some effect in this system, although the dominant effect of norepinephrine operates through cyclic AMP.

Although lighting is the synchronizer of this process, experiments have been done with animals housed in continuous darkness. Under these conditions, melatonin synthesis and secretion continue to exhibit circa-dian rhythms, which require sympathetic nerves innervating the pineal. Obviously another cycling signal exists, perhaps originating in the suprachiasmic nuclei of the brain. Estrogens may exert some influence on the system, modulating the production of melatonin, although the evidence is not strong. Melatonin clearly acts on the brain, but it may also act on the pituitary and other organs. In all species examined, melatonin has been found to reach peak concentrations in darkness in CSF, blood, and urine. Figure 18-8 shows the relative levels of pineal-produced substances as well as the concentrations of melatonin in plasma and urinary metabolites as a function of the hourly light-dark cycle.

Melatonin is cleared in the urine for the most part by way of the liver, which contains a microsomal enzyme catalyzing 6-hydroxylation. Following hydroxylation, some of the product becomes esterified with sulfate and is excreted in that form (Figure 18-9).

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