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Archives of Biochemistry and Biophysics Dec 2014Skin melanocytes and ocular pigment cells contain specialized organelles called melanosomes, which are responsible for the synthesis of melanin, the major pigment in... (Review)
Review
Skin melanocytes and ocular pigment cells contain specialized organelles called melanosomes, which are responsible for the synthesis of melanin, the major pigment in mammals. Defects in the complex mechanisms involved in melanin synthesis and regulation result in vision and pigmentation deficits, impaired development of the visual system, and increased susceptibility to skin and eye cancers. Ion transport across cellular membranes is critical for many biological processes, including pigmentation, but the molecular mechanisms by which it regulates melanin synthesis, storage, and transfer are not understood. In this review we first discuss ion channels and transporters that function at the plasma membrane of melanocytes; in the second part we consider ion transport across the membrane of intracellular organelles, with emphasis on melanosomes. We discuss recently characterized lysosomal and endosomal ion channels and transporters associated with pigmentation phenotypes. We then review the evidence for melanosomal channels and transporters critical for pigmentation, discussing potential molecular mechanisms mediating their function. The studies investigating ion transport in pigmentation physiology open new avenues for future research and could reveal novel molecular mechanisms underlying melanogenesis.
Topics: Animals; Calcium Signaling; Endosomes; Humans; Intracellular Membranes; Ion Channels; Ion Transport; Lysosomes; Melanins; Melanocytes; Melanosomes; Membrane Potentials; Pigmentation
PubMed: 25034214
DOI: 10.1016/j.abb.2014.06.020 -
International Journal of Molecular... Apr 2016The regulation of melanin production is important for managing skin darkness and hyperpigmentary disorders. Numerous anti-melanogenic agents that target tyrosinase... (Review)
Review
The regulation of melanin production is important for managing skin darkness and hyperpigmentary disorders. Numerous anti-melanogenic agents that target tyrosinase activity/stability, melanosome maturation/transfer, or melanogenesis-related signaling pathways have been developed. As a rate-limiting enzyme in melanogenesis, tyrosinase has been the most attractive target, but tyrosinase-targeted treatments still pose serious potential risks, indicating the necessity of developing lower-risk anti-melanogenic agents. Sugars are ubiquitous natural compounds found in humans and other organisms. Here, we review the recent advances in research on the roles of sugars and sugar-related agents in melanogenesis and in the development of sugar-based anti-melanogenic agents. The proposed mechanisms of action of these agents include: (a) (natural sugars) disturbing proper melanosome maturation by inducing osmotic stress and inhibiting the PI3 kinase pathway and (b) (sugar derivatives) inhibiting tyrosinase maturation by blocking N-glycosylation. Finally, we propose an alternative strategy for developing anti-melanogenic sugars that theoretically reduce melanosomal pH by inhibiting a sucrose transporter and reduce tyrosinase activity by inhibiting copper incorporation into an active site. These studies provide evidence of the utility of sugar-based anti-melanogenic agents in managing skin darkness and curing pigmentary disorders and suggest a future direction for the development of physiologically favorable anti-melanogenic agents.
Topics: Animals; Antigens, Neoplasm; Carbohydrates; Humans; Melanins; Membrane Transport Proteins; Skin Pigmentation
PubMed: 27092497
DOI: 10.3390/ijms17040583 -
Oncology Letters May 2019The process of melanin synthesis and distribution is called melanogenesis, a process that is based on melanocytes present among the basal cells of the epidermis.... (Review)
Review
The process of melanin synthesis and distribution is called melanogenesis, a process that is based on melanocytes present among the basal cells of the epidermis. Pigments formed in melanocyte melanosomes are then stored in the basal layer of epidermal cells, as well as in dermal macrophages, which become melanophores. From the embryological point of view, melanocytes derive from the melanoblasts of the neural crest, from where they migrate during the first months of life into the skin, eye, cochlea, bone, peripheral nervous system, heart and adipose tissue. The melanic pigments, eumelanin and pheomelanin, are the final product of complex biochemical reactions starting from the amino acid L-tyrosine. Melanin has a major role in skin homeostasis through the photoprotection it offers from the harmful effect of ultraviolet radiation. Melanin absorbs and/or reflects ultraviolet radiation but is also involved in the neutralizing process of free radicals and reactive oxygen species. Pigmentogenesis is a dependent oxygen process and is controlled by intrinsic factors (genetic and hormonal) as well as extrinsic factors (ultraviolet radiation). Melanogenesis is stimulated by stimulant melanocytic hormone, adrenocorticotropin hormone, estrogens and progesterone. The present review aimed to provide a summary of recent data about melanogenesis physiology.
PubMed: 30944614
DOI: 10.3892/ol.2019.10071 -
Journal of Pharmaceutical Analysis Oct 2020Tyrosinase is an important enzyme in controlling the formation of melanin in melanosome, and plays a key role in the pigmentation of hair and skin. The abnormal... (Review)
Review
Tyrosinase is an important enzyme in controlling the formation of melanin in melanosome, and plays a key role in the pigmentation of hair and skin. The abnormal expression or activation of tyrosinase is associated with several diseases such as albinism, vitiligo, melanoma and Parkinson disease. Excessive deposition of melanin could cause diseases such as freckles and brown spots in the human body, and it is also closely related to browning of fruits and vegetables and insect molting. Detecting and inhibiting the activity of tyrosinase is of extraordinary value in the progress of diagnosis and treatment of these diseases. Therefore, many selective optical detection probes and small molecular inhibitors have been developed, and have made significant contributions to the basic and clinical research on these diseases. In this paper, the detection and inhibition of tyrosinase and their application in whitening products are reviewed, with special emphasis on development of fluorescent probes and inhibitors. Hopefully, this review will help design more efficient and sensitive tyrosinase probes and inhibitors, as well as shed light on novel treatment of diseases such as melanoma.
PubMed: 33133725
DOI: 10.1016/j.jpha.2020.07.004 -
International Journal of Molecular... Nov 2022cAMP-PKA signaling plays a pivotal role in melanin synthesis and melanosome transport by responding to the binding of the α-melanocyte-stimulating hormone (α-MSH) to...
cAMP-PKA signaling plays a pivotal role in melanin synthesis and melanosome transport by responding to the binding of the α-melanocyte-stimulating hormone (α-MSH) to melanocortin-1 receptor (MC1R). Adenylate cyclases (ADCYs) are the enzymes responsible for the synthesis of cAMP from ATP, which comprises nine transmembrane isoforms (ADCYs 1-9) and one soluble adenylate cyclase (ADCY 10) in mammals. However, little is known about which and how ADCY isoforms regulate melanocyte generation, melanin biosynthesis, and melanosome transport in vivo. In this study, we have generated a series of single and double mutants of Adcy isoforms in zebrafish. Among them, and double mutants cause defects in melanosome dispersion but do not impair melanoblast differentiation and melanocyte regeneration during the embryonic or larval stages. Activation of PKA, the main effector of cAMP signaling, significantly ameliorates the defects in melanosome dispersion in and double mutants. Mechanistically, Adcy3a and Adcy5 regulate melanosome dispersion by activating kinesin-1 while inhibiting cytoplasmic dynein-1. In adult zebrafish, Adcy3a and Adcy5 participate in the regulation of the expression of microphthalmia transcription factor (Mitfa) and melanin synthesis enzymes Tyr, Dct, and Trp1b. The deletion of Adcy3a and Adcy5 inhibits melanin production and reduces pigmented melanocyte numbers, causing a defect in establishing adult melanocyte stripes. Hence, our studies demonstrate that Adcy3a and Adcy5 play essential but redundant functions in mediating α-MSH-MC1R/cAMP-PKA signaling for regulating melanin synthesis and melanosome dispersion.
Topics: Animals; Melanosomes; Zebrafish; Melanins; alpha-MSH; Melanocytes; Receptor, Melanocortin, Type 1; Mammals
PubMed: 36430661
DOI: 10.3390/ijms232214182 -
International Journal of Molecular... Apr 2021The production of melanin pigments by melanocytes and their quantity, quality, and distribution play a decisive role in determining human skin, eye, and hair color, and... (Review)
Review
The production of melanin pigments by melanocytes and their quantity, quality, and distribution play a decisive role in determining human skin, eye, and hair color, and protect the skin from adverse effects of ultraviolet radiation (UVR) and oxidative stress from various environmental pollutants. Melanocytes reside in the basal layer of the interfollicular epidermis and are compensated by melanocyte stem cells in the follicular bulge area. Various stimuli such as eczema, microbial infection, ultraviolet light exposure, mechanical injury, and aging provoke skin inflammation. These acute or chronic inflammatory responses cause inflammatory cytokine production from epidermal keratinocytes as well as dermal fibroblasts and other cells, which in turn stimulate melanocytes, often resulting in skin pigmentation. It is confirmed by some recent studies that several interleukins (ILs) and other inflammatory mediators modulate the proliferation and differentiation of human epidermal melanocytes and also promote or inhibit expression of melanogenesis-related gene expression directly or indirectly, thereby participating in regulation of skin pigmentation. Understanding of mechanisms of skin pigmentation due to inflammation helps to elucidate the relationship between inflammation and skin pigmentation regulation and can guide development of new therapeutic pathways for treating pigmented dermatosis. This review covers the mechanistic aspects of skin pigmentation caused by inflammation.
Topics: Aging; Cell Differentiation; Humans; Inflammation; Keratinocytes; Melanins; Melanocytes; Skin; Skin Pigmentation; Ultraviolet Rays
PubMed: 33921371
DOI: 10.3390/ijms22083970 -
F1000Research 2020Melanin pigments are responsible for human skin and hair color, and they protect the body from harmful ultraviolet light. The black and brown melanin pigments are... (Review)
Review
Melanin pigments are responsible for human skin and hair color, and they protect the body from harmful ultraviolet light. The black and brown melanin pigments are synthesized in specialized lysosome-related organelles called melanosomes in melanocytes. Mature melanosomes are transported within melanocytes and transferred to adjacent keratinocytes, which constitute the principal part of human skin. The melanosomes are then deposited inside the keratinocytes and darken the skin (a process called tanning). Owing to their dark color, melanosomes can be seen easily with an ordinary light microscope, and melanosome research dates back approximately 150 years; since then, biochemical studies aimed at isolating and purifying melanosomes have been conducted. Moreover, in the last two decades, hundreds of molecules involved in regulating melanosomal functions have been identified by analyses of the genes of coat-color mutant animals and patients with genetic diseases characterized by pigment abnormalities, such as hypopigmentation. In recent years, dynamic analyses by more precise microscopic observations have revealed specific functions of a variety of molecules involved in melanogenesis. This review article focuses on the latest findings with regard to the steps (or mechanisms) involved in melanosome formation and transport of mature melanosomes within epidermal melanocytes. Finally, we will touch on current topics in melanosome research, particularly on the "melanosome transfer" and "post-transfer" steps, and discuss future directions in pigment research.
Topics: Animals; Humans; Keratinocytes; Melanins; Melanocytes; Melanosomes; Skin; Skin Pigmentation
PubMed: 32595944
DOI: 10.12688/f1000research.24625.1 -
International Journal of Molecular... Dec 2020The epidermis is located in the outermost layer of the living body and is the place where external stimuli such as ultraviolet rays and microorganisms first come into... (Review)
Review
The epidermis is located in the outermost layer of the living body and is the place where external stimuli such as ultraviolet rays and microorganisms first come into contact. Melanocytes and melanin play a wide range of roles such as adsorption of metals, thermoregulation, and protection from foreign enemies by camouflage. Pigmentary disorders are observed in diseases associated with immunodeficiency such as Griscelli syndrome, indicating molecular sharing between immune systems and the machineries of pigment formation. Melanocytes express functional toll-like receptors (TLRs), and innate immune stimulation via TLRs affects melanin synthesis and melanosome transport to modulate skin pigmentation. TLR2 enhances melanogenetic gene expression to augment melanogenesis. In contrast, TLR3 increases melanosome transport to transfer to keratinocytes through Rab27A, the responsible molecule of Griscelli syndrome. TLR4 and TLR9 enhance tyrosinase expression and melanogenesis through p38 MAPK (mitogen-activated protein kinase) and NFκB signaling pathway, respectively. TLR7 suppresses microphthalmia-associated transcription factor (MITF), and MITF reduction leads to melanocyte apoptosis. Accumulating knowledge of the TLRs function of melanocytes has enlightened the link between melanogenesis and innate immune system.
Topics: Animals; Humans; Immunity, Innate; Melanins; Melanocytes; Melanosomes; Skin Pigmentation; Toll-Like Receptors
PubMed: 33371432
DOI: 10.3390/ijms21249769 -
Proceedings of the National Academy of... Oct 2023Most biocatalytic processes in eukaryotic cells are regulated by subcellular microenvironments such as membrane-bound or membraneless organelles. These natural...
Most biocatalytic processes in eukaryotic cells are regulated by subcellular microenvironments such as membrane-bound or membraneless organelles. These natural compartmentalization systems have inspired the design of synthetic compartments composed of a variety of building blocks. Recently, the emerging field of liquid-liquid phase separation has facilitated the design of biomolecular condensates composed of proteins and nucleic acids, with controllable properties including polarity, diffusivity, surface tension, and encapsulation efficiency. However, utilizing phase-separated condensates as optical sensors has not yet been attempted. Here, we were inspired by the biosynthesis of melanin pigments, a key biocatalytic process that is regulated by compartmentalization in organelles, to design minimalistic biomolecular condensates with emergent optical properties. Melanins are ubiquitous pigment materials with a range of functionalities including photoprotection, coloration, and free radical scavenging activity. Their biosynthesis in the confined melanosomes involves oxidation-polymerization of tyrosine (Tyr), catalyzed by the enzyme tyrosinase. We have now developed condensates that are formed by an interaction between a Tyr-containing peptide and RNA and can serve as both microreactors and substrates for tyrosinase. Importantly, partitioning of Tyr into the condensates and subsequent oxidation-polymerization gives rise to unique optical properties including far-red fluorescence. We now demonstrate that individual condensates can serve as sensors to detect tyrosinase activity, with a limit of detection similar to that of synthetic fluorescent probes. This approach opens opportunities to utilize designer biomolecular condensates as diagnostic tools for various disorders involving abnormal enzymatic activity.
Topics: RNA; Melanins; Monophenol Monooxygenase; Proteins; Peptides; Organelles
PubMed: 37871222
DOI: 10.1073/pnas.2310569120 -
Developmental Biology May 2019Skin pigmentation is a powerful defense against ultraviolet irradiation. Particularly in humans, the body surface needs to be widely covered by protective pigmentation,... (Review)
Review
Skin pigmentation is a powerful defense against ultraviolet irradiation. Particularly in humans, the body surface needs to be widely covered by protective pigmentation, and melanocytes, a major lineage of neural crest derivatives, have evolved several maneuvers to transfer melanin pigment to the skin. Recent studies with embryonic melanocytes of chickens and mice have revealed sequential events mediated by melanocytes to maximize the skin coverage by pigmentation. These processes include the migration of melanocyte precursors in the embryo, the microscopic uniform spacing of individual melanocytes, and melanosome transfer from melanocytes to keratinocytes. In particular, in vivo/ex vivo live-imaging techniques of melanosome transfer and a quantitative method to evaluate the distribution patterns of melanocytes have greatly advanced our understanding of how a limited number of cells can implement a maximal coverage of the large surface area of a developing body.
Topics: Animals; Cell Movement; Chick Embryo; Chickens; Humans; Melanins; Melanocytes; Melanosomes; Mice; Models, Biological; Neural Crest; Skin Pigmentation
PubMed: 29698617
DOI: 10.1016/j.ydbio.2018.04.016