Melatonin is a ubiquitous molecule present in almost every live being from bacteria to humans. In vertebrates, besides being produced in peripheral tissues and acting as an autocrine and paracrine signal, melatonin is centrally synthetized by a neuroendocrine organ, the pineal gland. Independently of the considered species, pineal hormone melatonin is always produced during the night and its production and secretory episode duration are directly dependent on the length of the night. As its production is tightly linked to the light/dark cycle, melatonin main hormonal systemic integrative action is to coordinate behavioral and physiological adaptations to the environmental geophysical day and season. The circadian signal is dependent on its daily production regularity, on the contrast between day and night concentrations, and on specially developed ways of action. During its daily secretory episode, melatonin coordinates the night adaptive physiology through immediate effects and primes the day adaptive responses through prospective effects that will only appear at daytime, when melatonin is absent. Similarly, the annual history of the daily melatonin secretory episode duration primes the central nervous/endocrine system to the seasons to come. Remarkably, maternal melatonin programs the fetuses' behavior and physiology to cope with the environmental light/dark cycle and season after birth. These unique ways of action turn melatonin into a biological time-domain-acting molecule. The present review focuses on the above considerations, proposes a putative classification of clinical melatonin dysfunctions, and discusses general guidelines to the therapeutic use of melatonin.

Melatonin as a hormone: new physiological and clinical insights

Melatonin Modulates Cell Survival of New Neurons in the Hippocampus of Adult Mice

In this article, we review the data concerning melatonin interactions with calmodulin. The kinetics of melatonin-calmodulin binding suggest that the hormone modulates cell activity through intracellular binding to the protein at physiological concentration ranges. Melatonin interaction with calmodulin may allow the hormone to modulate rhythmically many cellular functions. Melatonin's effect on tubulin polymerization, and cytoskeletal changes in MDCK and N1E-115 cells cultured with melatonin, suggest that at low concentrations (10−9 M) cytoskeletal effects are mediated by its antagonism to Ca2+-calmodulin. At higher concentrations (10−5 M), non-specific binding of melatonin to tubulin occurs thus overcoming the specific melatonin antagonism to Ca2+-calmodulin. Since the structures of melatonin and calmodulin are phylogenetically well preserved, calmodulin-melatonin interaction probably represents a major mechanism for regulation and synchronization of cell physiology.

https://link.springer.com/content/pdf/10.1007/BF01923944.pdf

Calmodulin mediates melatonin cytoskeletal effects

Binding of 3H-melatonin to calmodulin.

In vitro inhibition of Ca2+/calmodulin-dependent kinase II activity by melatonin

The fate of 3H-melatonin after its intracerebroventricular administration was studied both in different brain regions and in subcellular fractions. The rate of disappearance of 3H-melatonin from the brain was found to be multiphasic. Forty-eight h after a 3H-melatonin injection, radioactivity was still present in the brain. Nonlinear regression analysis of the data confirmed a very rapid half-life component and (t1/2 = 3.04 min) a slower one (t1/2 = 36 min). We also found a much slower component (t1/2 = 24 h), however. Considerable metabolism of melatonin was detected since only 36.5% of administered radioactivity remained as melatonin at 45 min. The subcellular distribution of the radioactivity present in the brain at all times studied showed that a major proportion of the radioactivity remained in the cytosol and respectively decreasing proportions in the 900g pellet, mitochondrial pellet, and the microsomes. The radioactivity remaining in the cytosol at 45 min was found to coelute with a macromolecule that was resolved by gel filtration and could be displaced by previous melatonin administration. Purified nuclei retained 0.71% of the radioactivity at 45 min; of this total, 73% was KCl extractable. Our data suggest the presence of a binding site in the cytosol and in the nucleus. The presence of 3H-melatonin up to 48 h after its administration may account for melatonin's long-term effects on brain function.

Bertha G. Ortega-Corona

Papers

Subneuronal Fate of Intracerebroventricular Injected 3H-Melatonin