Expression of genes coding melatonin and serotonin receptors in rodent skin

doi:10.1016/j.bbaexp.2004.09.002

Biochimica et Biophysica Acta (BBA) - Gene Structure and Expression

Volume 1680, Issue 2, 21 October 2004, Pages 67-70

https://doi.org/10.1016/j.bbaexp.2004.09.002 Get rights and content

Abstract

Targeted search for expression of melatonin and serotonin receptors genes in the skin of C57BL/6J mice showed expression of MT1B (but not MT1A). Mouse skin and hamster melanomas also expressed 5HT2B and 5HT7. We identified two novel isoforms of MT1A and 5HT7 (GenBank accession AY131266 and AY131265).

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MT1 and MT2 receptors are expressed both jointly and individually in various tissues of the body, not limited to the hypothalamic area [17–19]. MT1 receptor is widely distributed in the SCN [20], cerebral cortex [17], cerebellum [21], hippocampus [22], medial habenula [17], pituitary gland [23], ovary [24], testis [25], retina [26], liver and kidney [27], skin [28] and immune system [29]. MT2 receptor is more restrictively distributed and found mainly in the brain.
Alzheimer’s disease (AD) is an age-related neurodegenerative disease with multiple predisposing factors and complicated pathogenesis. Aβ peptide is one of the most important pathogenic factors in the etiology of AD. Accumulating evidence indicates that the imbalance of Aβ production and Aβ clearance in the brain of AD patients leads to Aβ deposition and neurotoxic Aβ oligomer formation. Melatonin shows a potent neuroprotective effect and can prevent or slow down the progression of AD, supporting the view that melatonin is a potential therapeutic molecule for AD. Melatonin modulates the regulatory network of secretase expression and affects the function of secretase, thereby inhibiting amyloidogenic APP processing and Aβ production. Additionally, melatonin ameliorates Aβ-induced neurotoxicity and probably promotes Aβ clearance through glymphatic-lymphatic drainage, BBB transportation and degradation pathways. In this review, we summarize and discuss the role of melatonin against Aβ-dependent AD pathogenesis. We explore the potential cellular and molecular mechanisms of melatonin on Aβ production and assembly, Aβ clearance, Aβ neurotoxicity and circadian cycle disruption. We summarize multiple clinical trials of melatonin treatment in AD patients, showing that melatonin has a promising effect on improving sleep quality and cognitive function. This review aims to stimulate further research on melatonin as a potential therapeutic agent for AD.
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Gene expression and production of alternatively spliced or aberrant forms of MT receptors is modulated by UVB and skin pathology (Slominski et al., 2003c, 2005a). In contrast, murine skin showed exclusive expression of the MT2 gene (Kobayashi et al., 2005; Slominski et al., 2004a). By immunocytochemistry, MT1 was detected in the differentiating layers of the epidermis, outer and inner root sheaths of the hair follicle (HF), eccrine glands, and blood vessels, whereas MT2 was detected in inner root sheath, eccrine glands, and blood vessels of human skin (Fischer et al., 2008a; Slominski et al., 2005a, 2005c).
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Citation Excerpt :
Serotonin (5-hydroxytryptamine, 5-HT) is a neurotransmitter whose actions are mediated via an interaction with receptors, including seven families (5-HT1–7 receptors) with at least 21 subtypes. Skin cells express mRNA encoding 5-HT receptors, including 5-HT1A, -1B, -2A, -2B, -2C and -7 receptors (Slominski et al., 2004a, 2003b). 5-HT2A receptor was reported participating in the regulatory processes of 5-HT on melanogenesis (Lee et al., 2011).
Skin pigmentation is a complex process controlled by many different factors. Substance P (SP) regulates many biological functions, including melanogenesis and stress. Our previous study indicated that regulation of SP on melanocyte function was mediated by neurokinin 1 receptor (NK₁ receptor). Substantial evidence has accumulated that psychological stress can be associated with skin pigmentation, so that the impact of 5-hydroxytryptamine (5-HT), one of the important factors participating in stress process, on melanogenesis has also been concerned. It has been reported that 5-HT induces melanin synthesis via 5-HT_2A receptor. Furthermore, 5-HT_2A receptor and NK₁ receptor are G-protein coupled receptors (GPCRs) and both expressed on melanocyte, the present study was designed to investigate whether SP has influence on the adjustment function of 5-HT. Our data demonstrated that, SP inhibited 5-HT_2A receptor expression to neutralize the pro-melanogenesis effect of 5-HT on B16F10 cells. The up-regulation of NK₁ receptor expression was simultaneous with the down-regulation of 5-HT_2A receptor treated by SP. This inhibition of 5-HT_2A receptor expression by SP could be reversed by NK₁ receptor antagonist Spantide I. Our studies indicated that SP could directly induce B16F10 cells apoptosis in vitro. 5-HT and 5-HT_2A receptor agonist could mitigate this apoptotic effect of SP. It is the strong evidence of possible cross-talk between GPCRs and giving enlightenments when screening desirable drugs for target receptors.
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Citation Excerpt :
Gene expression of 5-HT2BR and 5-HT2CR has previously been described in different human melanoma cell lines [19]. Moreover, 5-HT2BR mRNA was found in mouse and hamster melanomas [42] which is compatible with the observation in human skin that this receptor represents the predominant species expressed in the majority of skin cells [19]. Effects of serotonin on human tumour cells have been evaluated by several authors in recent years [13,43–47]; however, it has remained controversial whether, in this context, serotonin promotes or inhibits tumour growth.
Mast cells are key effectors of the immune system and are involved in a variety of physiological and pathophysiological processes. Dermal mast cells have been demonstrated to degranulate as a consequence of ionizing radiation exposure. Mast cells accumulate at the periphery of skin tumours including malignant melanoma. Melanoma cells thus represent a potential target for the action of mediators released from irradiated mast cells.
In this study, we evaluated the effects of serotonin and ionizing radiation on the proliferation and the adhesion molecule expression of malignant melanoma cells.
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2012, Molecular and Cellular Endocrinology
Citation Excerpt :
The fur growth in rodents may be mediated by melatonin binding sites/receptors expressed in hair follicles, since these were identified in the murine skin showing hair cycle dependent pattern of expression (Kobayashi et al., 2005; Slominski et al., 1994). Also melatonin has been found to promote the anagen phase of murine hair cycle and these actions seem to be mediated by the MT2 receptor, as this is the predominate receptor in the cells of question (Kobayashi et al., 2005; Slominski et al., 2004a). These findings prompted a randomized, double-blind study of hair growth in women suffering from androgenic alopecia.
Many of melatonin’s actions are mediated through interaction with the G-protein coupled membrane bound melatonin receptors type 1 and type 2 (MT1 and MT2, respectively) or, indirectly with nuclear orphan receptors from the RORα/RZR family. Melatonin also binds to the quinone reductase II enzyme, previously defined the MT3 receptor. Melatonin receptors are widely distributed in the body; herein we summarize their expression and actions in non-neural tissues. Several controversies still exist regarding, for example, whether melatonin binds the RORα/RZR family. Studies of the peripheral distribution of melatonin receptors are important since they are attractive targets for immunomodulation, regulation of endocrine, reproductive and cardiovascular functions, modulation of skin pigmentation, hair growth, cancerogenesis, and aging. Melatonin receptor agonists and antagonists have an exciting future since they could define multiple mechanisms by which melatonin modulates the complexity of such a wide variety of physiological and pathological processes.
Melatonin-A pleiotropic, orchestrating regulator molecule
2011, Progress in Neurobiology
Citation Excerpt :
Because of considerable species differences in receptor distribution, the following section will mainly focus on human tissues, with reference to receptor subtype as far as this has been identified. Among the peripheral organs, the membrane receptors were demonstrated in duodenal enterocytes (MT2, Sjöblom et al., 2001, 2003; Flemström et al., 2003, 2010; Flemström and Sjöblom, 2005; Sjöblom, 2005), colon, caecum and appendix (subtype not identified, Poon et al., 1996, 1997), gallbladder epithelium (MT1, Aust et al., 2004), parotid gland (MT1, MT2, Aras and Ekström, 2008), exocrine pancreas (MT1, Aust et al., 2008), β cells of endocrine pancreas (MT1, MT2, Mühlbauer and Peschke, 2007; Ramracheya et al., 2008; Lyssenko et al., 2009; Mulder et al., 2009), skin (MT1, MT2, Slominski et al., 2002, 2003, 2004), breast epithelium (Dillon et al., 2002), myometrium (MT1, MT2, Schlabritz-Loutsevitch et al., 2003; Sharkey et al., 2010), placenta (MT1, MT2, Lanoix et al., 2006), granulosa and luteal cells (MT1, MT2, Yie et al., 1995; Niles et al., 1999; Woo et al., 2001; Tamura et al., 2009), fetal kidney (MT1, Williams et al., 2001), cardiac ventricular wall (MT1, MT2, Ekmekcioglu et al., 2001, 2003), aorta, coronary and cerebral arteries and other parts of peripheral vasculature (MT1, MT2, Savaskan et al., 2001; Ekmekcioglu et al., 2001, 2003; Ekmekcioglu, 2006; Cui et al., 2008), brown and white adipose tissues (MT1, MT2, Brydon et al., 2001; Ekmekcioglu, 2006), platelets (subtype not identified, Vacas et al., 1992), and various immune cells (MT1, perhaps also MT2, Konakchieva et al., 1995; García-Pergañeda et al., 1997; Pozo et al., 2004; Carrillo-Vico et al., 2003b; Lardone et al., 2009). Additional information exists on the expression of MT1 and MT2 in various human cancer cell lines of different origin (Xi et al., 2000; Dillon et al., 2002; Ekmekcioglu, 2006; Lanoix et al., 2006; Aust et al., 2008; Nakamura et al., 2008; Carbajo-Pescador et al., 2009).
Melatonin, the neurohormone of the pineal gland, is also produced by various other tissues and cells. It acts via G protein-coupled receptors expressed in various areas of the central nervous system and in peripheral tissues. Parallel signaling mechanisms lead to cell-specific control and recruitment of downstream factors, including various kinases, transcription factors and ion channels. Additional actions via nuclear receptors and other binding sites are likely. By virtue of high receptor density in the circadian pacemaker, melatonin is involved in the phasing of circadian rhythms and sleep promotion. Additionally, it exerts effects on peripheral oscillators, including phase coupling of parallel cellular clocks based on alternate use of core oscillator proteins. Direct central and peripheral actions concern the up- or downregulation of various proteins, among which inducible and neuronal NO synthases seem to be of particular importance for antagonizing inflammation and excitotoxicity. The methoxyindole is also synthesized in several peripheral tissues, so that the total content of tissue melatonin exceeds by far the amounts in the circulation. Emerging fields in melatonin research concern receptor polymorphism in relation to various diseases, the control of sleep, the metabolic syndrome, weight control, diabetes type 2 and insulin resistance, and mitochondrial effects. Control of electron flux, prevention of bottlenecks in the respiratory chain and electron leakage contribute to the avoidance of damage by free radicals and seem to be important in neuroprotection, inflammatory diseases and, presumably, aging. Newly discovered influences on sirtuins and downstream factors indicate that melatonin has a role in mitochondrial biogenesis.

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Rapid reportExpression of genes coding melatonin and serotonin receptors in rodent skin

Abstract

J. Chromatogr., B, Biomed. Sci. Appl.

Lancet

J. Biol. Chem.

J. Invest. Dermatol.

FEBS Lett.

J. Dermatol. Sci.

Melatonin Biosynthesis, Physiological Effects, and Clinical Implications

Serotoninergic and melatoninergic systems are fully expressed in human skin

FASEB J.

Rapid report
Expression of genes coding melatonin and serotonin receptors in rodent skin