Chapter 8 - Melatonin: A Multitasking Molecule

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Abstract

Melatonin (N-acetyl-5-methoxytryptamine) has revealed itself as an ubiquitously distributed and functionally diverse molecule. The mechanisms that control its synthesis within the pineal gland have been well characterized and the retinal and biological clock processes that modulate the circadian production of melatonin in the pineal gland are rapidly being unravelled. A feature that characterizes melatonin is the variety of mechanisms it employs to modulate the physiology and molecular biology of cells. While many of these actions are mediated by well-characterized, G-protein coupled melatonin receptors in cellular membranes, other actions of the indole seem to involve its interaction with orphan nuclear receptors and with molecules, for example calmodulin, in the cytosol. Additionally, by virtue of its ability to detoxify free radicals and related oxygen derivatives, melatonin influences the molecular physiology of cells via receptor-independent means. These uncommonly complex processes often make it difficult to determine specifically how melatonin functions to exert its obvious actions. What is apparent, however, is that the actions of melatonin contribute to improved cellular and organismal physiology. In view of this and its virtual absence of toxicity, melatonin may well find applications in both human and veterinary medicine.

Introduction

Identification of the pineal gland as a genuine organ of internal secretion was established by the isolation and identification of the methoxy derivative of serotonin, that is N-acetyl-5-methoxytryptamine, in bovine pineal tissue by Lerner et al., 1958, Lerner et al., 1959 in the late 1950s. The newly discovered molecule was named melatonin because of its effects on melanin (‘mela-’) aggregation in the melanocytes of amphibians and its derivation from serotonin (‘-tonin’). Soon after its discovery, its synthetic pathway in the pineal gland was identified (Axelrod and Weissbach, 1960).

One of the earliest findings regarding the production of melatonin in the pineal is that it is primarily synthesized and secreted at night and that the circadian rhythm of melatonin production is determined by the prevailing light–dark cycle (Axelrod et al., 1965). As a consequence, nocturnal circulating melatonin levels are higher at night than during the day in all species examined.

Besides the pineal gland, many organs may have the capability of producing melatonin given the high levels they contain (Hardeland, 2009); however, the diurnal rhythm of blood melatonin is exclusively a function of its secretion by the pineal gland. Of interest is that, in addition to the blood, melatonin is detectable in other fluids as well, for example fluid of the anterior chamber of the eye (Yu et al., 1990), cerebrospinal fluid (CSF) (Skinner and Malpaux, 1999), bile (Tan et al., 1999), ovarian follicular fluid (Nakamura et al., 2003), and so on. Moreover, these fluids often have concentrations much higher than in the serum suggesting that melatonin is either concentrated against a gradient or that melatonin in these fluids is not derived from the blood vascular system. The unexpectedly wide distribution of melatonin in the organs and fluids of mammals also portends equally diverse actions, some of which are summarized in this brief review.

Section snippets

Melatonin synthesis, release and catabolism

The metabolic pathway of tryptophan that culminates in melatonin generation is well known (Fig. 1). The quantity of serotonin in the gland is determined by the activity of tryptophan hydroxylase (TPH). The expression of TPH mRNA as well as the activity of the enzyme vary over a light–dark cycle and are clock-driven rhythms; peak levels of both occur at night (Sugden, 2003) coincident with maximal melatonin generation. The amount of serotonin in the pineal gland is reportedly exceptionally high,

Melatonin synthesis: light regulation

Substantial progress has been made in the last decade in our understanding as to how environmental light relates to the biological clock, the SCN, and pineal melatonin synthesis. Of great interest is that the conventional retinal photoreceptors, that is the rods and cones, have only a minor role in the light-mediated inhibition of pineal melatonin production. Rather, a highly specialized group of retinal ganglion cells which constitute 1–2% of the total number of neurons in the ganglion cell

Melatonin: receptors and signal transduction mechanisms

Melatonin influences cellular physiology via membrane receptors, nuclear binding sites and after its interaction with cytosolic molecules. Additionally, melatonin has receptor-independent actions by virtue of its ability to directly scavenge menacing free radicals and related reactants. Much of what is known concerning the regulatory actions of melatonin stems from its binding to receptors in the cell membrane. Although originally thought to have a rather limited distribution, with more

Melatonin and seasonal reproduction

In animals living under natural conditions, conveying information about the changing ambient photoperiod duration is one of the essential functions of the melatonin rhythm. Thus, the cyclic production of melatonin not only functions as a ‘clock’but also as a ‘calendar’ (Reiter, 1993). This latter function is achieved due to the fact that as night length changes, the duration of the nocturnal elevation of melatonin likewise increases or decreases in length accordingly (Brainard et al., 1982).

Melatonin, circadian rhythms and sleep

The SCN was one of the earliest sites in which melatonin receptors were identified (Dubocovich and Markowska, 2005). The mammalian SCN as well as immortalized SCN2.2 neurons express mRNA and protein for both the MT1 and MT2 membrane receptors (Rivera-Bermudez et al., 2004). As in other tissues, the actions of melatonin on its receptors in the SCN involve multiple signalling pathways (Liu et al., 1997).

In SCN2.2 cells, melatonin inhibits forskolin-stimulated cAMP accumulation with this response

Melatonin and cancer inhibition

While the majority of published reports have been concerned with the ability of melatonin to inhibit the progression of already established tumours, there is also evidence that melatonin may reduce events that lead to the initiation of cancer. Thus, many tumours develop following damage to nuclear DNA when it goes unrepaired. Injury to DNA is frequently a result of free radicals (Cerutti et al., 1994). Since melatonin readily neutralizes free radicals, it protects DNA from the oxidative damage

Melatonin as a free radical scavenger and antioxidant

The ability of melatonin to quench the devastatingly reactive and toxic •OH was initially uncovered in 1993 (Tan et al., 1993). Since then, this action of melatonin has been repeatedly confirmed (Tan et al., 2002). Moreover, in addition to neutralizing the •OH, melatonin has been found to detoxify other damaging oxidizing agents including the ONOO, O2•–, H2O2, 1O2, NO•, LOO• and HClO (Reiter et al., 2009d). Of significant interest and importance are the observations that not only is melatonin

Concluding remarks

Melatonin is a remarkably functionally pleiotropic neuroendocrine molecule with actions mediated by membrane receptors, cytosolic and nuclear binding sites and via its receptor-independent functions. In some cases it is difficult to determine by which of these processes melatonin mediates its effects. The fact that melatonin is produced in all species of the animal kingdom from unicells to humans suggests its early evolution and functional importance. While in humans it is widely known that

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