It was recently discovered that mammalian skin can produce serotonin and transform it into melatonin. Pathways for the biosynthesis and biodegradation of serotonin and melatonin have been characterized in human and rodent skin and in their major cellular populations. Moreover, receptors for serotonin and melatonin receptors are expressed in keratinocytes, melanocytes, and fibroblasts and these mediate phenotypic actions on cellular proliferation and differentiation. Melatonin exerts receptor-independent effects, including activation of pathways protective of oxidative stress and the modification of cellular metabolism. While serotonin is known to have several roles in skin-e.g., pro-edema, vasodilatory, proinflammatory, and pruritogenic-melatonin has been experimentally implicated in hair growth cycling, pigmentation physiology, and melanoma control. Thus, the widespread expression of a cutaneous seorotoninergic/melatoninergic syste,m(s) indicates considerable selectivity of action to facilitate intra-, auto-, or paracrine mechanisms that define and influence skin function in a highly compartmentalized manner. Notably, the cutaneous melatoninergic system is organized to respond to continuous stimulation in contrast to the pineal gland, which (being insulated from the external environment) responds to discontinuous activation by the circadian clock. Overall, the cutaneous serotoninergic/melatoninergic system could counteract or buffer external (environmental) or internal stresses to preserve the biological integrity of the organ and to maintain its homeostasis.-Slominski, A. J., Wortsman, J., Tobin, D. J. The cutaneous serotoninergic/melatoninergic system: securing a place under the sun.

The cutaneous serotoninergic/melatoninergic system: securing a place under the sun

Serotonin (5-hydroxytryptamine; 5-HT) is an important mediator of bidirectional interactions between the neuroendocrine system and the skin. The rate of synthesis of 5-HT from l-tryptophan can be enhanced by brain-derived neuronal growth factor, cytokines, exposure to ultraviolet light and steroids. The major source of 5-HT in the skin are platelets, which, upon aggregation, release this biogenic amine. Moreover, the epidermal and dermal skin express the enzymes required for the transformation of tryptophan to 5-HT, and certain skin cells, such as melanocytes, have been demonstrated to produce 5-HT. In addition, rodent mast cells produce 5-HT, but human mast cells have not yet been fully examined in this respect. Skin cells express functionally active, membrane-bound receptors for 5-HT, as well as proteins that transport 5-HT. The interactions of 5-HT with these various proteins determines the nature, magnitude and duration of serotonergic responses. The immune and vasculature systems in the skin are traditional targets for bioregulation by 5-HT. Moreover, recent findings indicate that keratinocytes, melanocytes and dermal fibroblasts also respond to this amine in various ways. Thus, mammalian skin is both a site for the production of and a target for bioregulation by 5-HT. This indicates that agonists and antagonists directed towards specific 5-HT receptors could be useful in connection with treatment of skin diseases. Based on our increasing knowledge concerning these receptors and their plasticity, future research will focus on the development of serotonergic drugs that exert metabotrophic effects on the cells of the skin without affecting the central nervous system.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1600-0625.2007.00670.x

The skin as a mirror of the soul: exploring the possible roles of serotonin.

Motivation: The importance of chemical compounds has been emphasized more in molecular biology, and 'chemical genomics' has attracted a great deal of attention in recent years. Thus an important issue in current molecular biology is to identify biological-related chemical compounds (more specifically, drugs) and genes. Co-occurrence of biological entities in the literature is a simple, comprehensive and popular technique to find the association of these entities. Our focus is to mine implicit 'chemical compound and gene' relations from the co-occurrence in the literature.

Results: We propose a probabilistic model, called the mixture aspect model (MAM), and an algorithm for estimating its parameters to efficiently handle different types of co-occurrence datasets at once. We examined the performance of our approach not only by a cross-validation using the data generated from the MEDLINE records but also by a test using an independent human-curated dataset of the relationships between chemical compounds and genes in the ChEBI database. We performed experimentation on three different types of co-occurrence datasets (i.e. compound--gene, gene--gene and compound--compound co-occurrences) in both cases. Experimental results have shown that MAM trained by all datasets outperformed any simple model trained by other combinations of datasets with the difference being statistically significant in all cases. In particular, we found that incorporating compound--compound co-occurrences is the most effective in improving the predictive performance. We finally computed the likelihoods of all unknown compound--gene (more specifically, drug--gene) pairs using our approach and selected the top 20 pairs according to the likelihoods. We validated them from biological, medical and pharmaceutical viewpoints.

Contact: mami@kuicr.kyoto-u.ac.jp

/pdf/a-probabilistic-model-for-mining-implicit-chemical-compound-17m80jqdbi.pdf

A probabilistic model for mining implicit ‘chemical compound–gene’ relations from literature

We showed expression of the tryptophan hydroxylase gene and of tryptophan hydroxylase protein immunoreactivity in mouse skin and skin cells. Extracts from skin and melanocyte samples acetylated serotonin to N-acetylserotonin and tryptamine to N-acetyltryptamine. A different enzyme from arylalkylamine N-acetyltransferase mediated this reaction, as this gene was defective in the C57BL6 mouse, coding predominantly for a protein without enzymatic activity. Serotonin (but not tryptamine) acetylation varied according to hair cycle phase and anatomic location. Serotonin was also metabolized to 5-hydroxytryptophol and 5-hydroxyindole acetic acid, probably through stepwise transformation catalyzed by monoamine oxidase, aldehyde dehydrogenase and aldehyde reductase. Activity of the melatonin-forming enzyme hydroxyindole-O-methyltransferase was notably below detectable levels in all samples of mouse corporal skin, although it was detectable at low levels in the ears and in Cloudman melanoma (derived from the DBA/2 J mouse strain). In conclusion, mouse skin has the molecular and biochemical apparatus necessary to produce and metabolize serotonin and N-acetylserotonin, and its activity is determined by topography, physiological status of the skin, cell type and mouse strain.

https://febs.onlinelibrary.wiley.com/doi/pdf/10.1046/j.1432-1033.2003.03708.x

Characterization of the serotoninergic system in the C57BL/6 mouse skin.

Tryptophan hydroxylase expression in human skin cells.

Previously we demonstrated that tryptophan hydroxylase (TPH) undergoes very fast turnover driven by ATP-dependent proteolysis in serotonin producing mast cells [Hasegawa et al. (1995) FEBS Lett. 368, 151-154]. We searched for the major proteases involved in the rapid degradation of TPH in RBL2H3 cells. Among various protease inhibitors tested, proteasome inhibitors MG115, MG101, MG132, and lactacystin effectively inhibited the intracellular degradation of TPH. Administration of the proteasome inhibitors to cultured cells caused more than a 5-fold accumulation of TPH. Administration of the inhibitors together with cycloheximide stabilized the amount of TPH with no appreciable increase or decrease. Although MG-series proteasome inhibitors could inhibit calpain, the involvement of calpain was excluded since the cysteine protease inhibitor E-64-d, which acts on calpain, had no effect. Extracts of RBL2H3 cells were shown to contain a protease that digests TPH in an ATP-dependent manner and is sensitive to proteasome inhibitors. The ubiquitination of TPH could be visualized by Western blot analysis using both anti-TPH and anti-ubiquitin antibodies. Based on these results, we conclude that 26S proteasomes are mainly involved in the degradation of TPH. In the reported amino acid sequences of TPH from various sources including human, rabbit, rat, and mouse, a PEST sequence that is widely shared among short-lived proteins has been recognized. It was noted that the PEST sequence lies within the most conserved portion of the enzyme, the pteridine binding site.

Rapid Turnover of Tryptophan Hydroxylase Is Driven by Proteasomes in RBL2H3 Cells, a Serotonin Producing Mast Cell Line

The contents of tryptophan (Trp) metabolites and the activities of the enzymes involved in ommochrome biosynthesis were measured in an albino strain of a terrestrial isopod Armadillidium vulgare. There was little difference between the Trp content in the albino mutant and that in the wild type, although the contents of 3-hydroxykynurenine (3-OH-Kyn), 3-hydroxyanthranilic acid (3-OH-AA) and xanthommatin in the albino were significantly lower than those in the wild type. Tryptophan 2,3-dioxygenase (TDO) activity in the albino was extremely low, while the activities of Kyn-3-hydroxylase and kynureninase did not differ significantly between the two phenotypes. The extremely low activity of TDO is probably one of main reasons why almost no ommochrome pigment is produced in the albino mutant.

Ommochrome genesis in an albino strain of a terrestrial isopod.

In order to clarify the cause of ommochrome deficiency in an albino strain of the terrestrial isopod, Armadillidium vulgare, levels of xanthommatin, 3-hydroxykynurenine, 3-hydroxyanthranilic acid and tryptophan in whole body extracts of the albino and the wild type individuals were determined together with enzyme activities of kynurenine-3-hydroxylase, kynureninase and tryptophan-2,3-dioxygenase Xanthommatin could not be detected in the albinos The levels of 3-hydroxykynurenine and 3-hydroxyanthranilic acid were determined by high-performance liquid chromatography (HPLC) with electrochemical detection and were markedly low in the albinos compared with the wild type individuals In contrast to those, the tryptophan levels determined by HPLC with fluorescence detection did not differ significantly between the two phenotypes In the albino A vulgare, kynurenine-3-hydroxylase activity was lower and kynureninase activity was higher than in the wild type, although the differences were not statistically significant Tryptophan-2,3-dioxygenase activity in the albinos was less than 10% that in the wild type Thus, ommochrome deficiency in the albino A vulgare is considered to be caused by the extremely low activity of tryptophan-2,3-dioxygenase

Rie Ikeda

Papers

Rapid Turnover of Tryptophan Hydroxylase Is Driven by Proteasomes in RBL2H3 Cells, a Serotonin Producing Mast Cell Line

Ommochrome genesis in an albino strain of a terrestrial isopod.

Ommochrome deficiency in an albino strain of a terrestrial isopod, Armadillidium vulgare.