Melatonin Uptake by Cells: An Answer to Its Relationship with Glucose?

Abstract

Melatonin, N-acetyl-5-methoxytryptamine, is an indole mainly synthesized from tryptophan in the pineal gland and secreted exclusively during the night in all the animals reported to date. While the pineal gland is the major source responsible for this night rise, it is not at all the exclusive production site and many other tissues and organs produce melatonin as well. Likewise, melatonin is not restricted to vertebrates, as its presence has been reported in almost all the phyla from protozoa to mammals. Melatonin displays a large set of functions including adaptation to light: dark cycles, free radical scavenging ability, antioxidant enzyme modulation, immunomodulatory actions or differentiation–proliferation regulatory effects, among others. However, in addition to those important functions, this evolutionary ‘ancient’ molecule still hides further tools with important cellular implications. The major goal of the present review is to discuss the data and experiments that have addressed the relationship between the indole and glucose. Classically, the pineal gland and a pinealectomy were associated with glucose homeostasis even before melatonin was chemically isolated. Numerous reports have provided the molecular components underlying the regulatory actions of melatonin on insulin secretion in pancreatic beta-cells, mainly involving membrane receptors MTNR1A/B, which would be partially responsible for the circadian rhythmicity of insulin in the organism. More recently, a new line of evidence has shown that glucose transporters GLUT/SLC2A are linked to melatonin uptake and its cellular internalization. Beside its binding to membrane receptors, melatonin transportation into the cytoplasm, required for its free radical scavenging abilities, still generates a great deal of debate. Thus, GLUT transporters might constitute at least one of the keys to explain the relationship between glucose and melatonin. These and other potential mechanisms responsible for such interaction are also discussed here.

Melatonin-Nrf2 Signaling Activates Peroxisomal Activities in Porcine Cumulus Cell-Oocyte Complexes

“…our study shows that melatonin can improve porcine oocyte quality and subsequent embryonic development through its various biological activities [10,40,41]. Melatonin is thought to mediate its effect by binding to receptors on the membrane, i.e., MTs [42], which constitute a superfamily of guanine nucleotide binding protein (G-protein)-coupled receptors [43,44]. Specifically, MT2 was found to be fundamentally involved in oocyte maturation, embryo development, and the activation of antioxidant-related signaling in porcine oocytes and embryos [8,40]; accordingly, our results showed that the regulation of MT2 resulted in differences in mRNA and protein levels among the treatment groups.…”

Transcriptomic Insights into the Effect of Melatonin in Saccharomyces cerevisiae in the Presence and Absence of Oxidative Stress

“…In vertebrates, several of the functions of melatonin are mediated by its membrane receptors [ 43 ], but others are receptor-independent, such as antioxidant activity, for which melatonin is required to penetrate the cell and enter intracellular compartments [ 44 ]. In humans, melatonin is suggested to cross membranes by passive diffusion and through transporters of glucose [ 45 ] or oligopeptides [ 46 , 47 ]. Moreover, as the membrane is the first barrier that separates the cell from the environment, it is one of the main targets of oxidative stress, which alters its lipidic composition.…”

“…Another possible route through which melatonin may enter the cell is potentially through some membrane transporters, such as those for urea or polyamines ( DUR3 ) (as they present a similar structure to melatonin), the oligopeptide transporter OPT1 , or the maltose permease MAL31 , the last two of which were upregulated by melatonin in presence and absence of oxidative stress ( Figure 1 E). Huo et al [ 46 ] recently described the possible involvement of PEPT1/2 oligopeptide transporters in the uptake of melatonin in mammalian cells, and a new line of evidence has shown that glucose transporters are linked to melatonin uptake in human cells [ 45 , 47 ]. Indeed, our results showed that some genes encoding carbohydrate and carbon source transporters were upregulated by the presence of melatonin in stressed cells ( HXT5, HXT6, HUT1, JEN1 , Dataset S4 ), which could also be related to melatonin internalization.…”

Validation of an Ex Vivo Permeation Method for the Intestinal Permeability of Different BCS Drugs and Its Correlation with Caco-2 In Vitro Experiments

“…This could be related to the intestinal accumulation of Mel described in mammals [30], where Mel intestinal receptors MT1 and MT2 are involved in multiple roles, such as regulation of gastrointestinal motility and epithelial permeability [31]. It could also be explained by the fact that Mel, although it exhibits protein-facilitated transport [32], reduces the duodenal epithelial paracellular permeability [33]. This may justify the P app value of 2.31 ± 0.12 × 10 −6 cm/s (n = 4) for Mel obtained by other authors in an ex vivo permeation through rat jejunum in small diffusion chambers [34], which is also a lower and statistically different value than Caco-2.…”