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Melanin Pigmentation in Mammalian Skin and Its Hormonal Regulation

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Melanin Pigmentation in Mammalian Skin and Its Hormonal Regulation Physiol Rev 84: 1155–1228, 2004; 10.1152/physrev.00044.2003. Melanin Pigmentation in Mammalian Skin and Its Hormonal Regulation ANDRZEJ SLOMINSKI, DESMOND J. TOBIN, SHIGEKI SHIBAHARA, AND JACOBO WORTSMAN Department of Pathology, University of Tennessee, Memphis, Tennessee; Department of Biomedical Sciences, University of Bradford, Bradford, West Yorkshire, United Kingdom; Department of Molecular Biology and Applied Physiology, Tohoku University School of Medicine, Sendai, Miyagi, Japan; and Department of Medicine, Southern Illinois University, Springfield, Illinois I. Melanin Pigment 1156 A. Melanins: chemical and physical properties 1156 B. Melanin pigment in skin physiology and pathology 1158 II. Biochemistry and Cellular and Molecular Biology of Melanogenesis 1160 A. Melanocytes as Melanin-Producing cells: cell biology and ultrastructure 1160 B. Biochemistry of melanogenesis 1163 C. Extrapigmentary functions of melanogenesis-related proteins 1168 III. Mechanisms of Regulation of Melanogenesis 1169 A. Transcriptional regulation 1169 B. Intracellular signal transduction pathways 1169 C. Dual function of L-tyrosine and L-DOPA: reaction substrates and bioregulators 1171 D. Summary 1174 IV. Hormonal Stimulators of Melanogenesis and Their Receptors 1174 A. G protein-coupled receptors and ligands 1174 B. SCF and its receptor 1184 C. Nuclear receptors and their ligands 1186 D. Other positive regulators of melanogenesis: bone morphogenic proteins 1188 E. Summary 1189 V. Hormonal Inhibitors of Melanogenesis and Receptors 1189 A. G protein-coupled receptors and their ligands 1189 B. Melanocortins antagonists 1192 C. Cytokines, growth factors, and receptors 1194 D. Other negative regulators of melanogenesis 1196 E. Summary 1197 VI. Miscellaneous Regulation of Melanogenesis By Nuclear Receptors and Their Ligands 1197 A. Glucocorticoids and their receptors 1197 B. Retinoids and their receptors 1198 C. Summary 1198 VII. Functional Regulation of Follicular (Hair) and Epidermal Melanin Units 1199 A. The epidermal melanin unit 1199 B. Regulation of hair cycle-coupled follicular melanogenesis 1200 VIII. Unified Concept for the Transcriptional Regulation of Melanogenesis: a Key Role for Microphtalmia-Associated Transcription Factor 1201 IX. Melanogenesis as Molecular Sensor and Transducer of Environmental Signals and Regulator of Local Homeostasis 1203 X. Comments and Future Directions 1205 Slominski, Andrzej, Desmond J. Tobin, Shigeki Shibahara, and Jacobo Wortsman. Melanin Pigmentation in Mammalian Skin and Its Hormonal Regulation. Physiol Rev 84: 1155-1228, 2004; 10.1152/physrev.00044.2003.— Cutaneous melanin pigment plays a critical role in camouflage, mimicry, social communication, and protection against harmful effects of solar radiation. Melanogenesis is under complex regulatory control by multiple agents interacting via pathways activated by receptor-dependent and -independent mechanisms, in hormonal, auto-, para-, or intracrine fashion. Because of the multidirectional nature and heterogeneous character of the melanogenesis modifying agents, its controlling factors are not organized into simple linear sequences, but they interphase instead www.prv.org 0031-9333/04 $15.00 Copyright © 2004 the American Physiological Society 1155 1156 SLOMINSKI, TOBIN, SHIBAHARA, AND WORTSMAN in a multidimensional network, with extensive functional overlapping with connections arranged both in series and in parallel. The most important positive regulator of melanogenesis is the MC1 receptor with its ligands melano- cortins and ACTH, whereas among the negative regulators agouti protein stands out, determining intensity of melanogenesis and also the type of melanin synthesized. Within the context of the skin as a stress organ, melanogenic activity serves as a unique molecular sensor and transducer of noxious signals and as regulator of local homeostasis. In keeping with these multiple roles, melanogenesis is controlled by a highly structured system, active since early embryogenesis and capable of superselective functional regulation that may reach down to the cellular level represented by single melanocytes. Indeed, the significance of melanogenesis extends beyond the mere assignment of a color trait. I. MELANIN PIGMENT L-tyrosine, which is then hydroxylated to L-dihydroxyphe- nylalanine (L-DOPA) (obligatory step both in vitro and in A. Melanins: Chemical and Physical Properties vivo). L-DOPA serves as a precursor to both melanins and catecholamines, acting along separate pathways (Fig. 1). Melanins, the end-products of complex multistep The next step, oxidation of L-DOPA to dopaquinone, is transformations of L-tyrosine, are polymorphous and mul- common to both eu- and pheomelanogenic pathways tifunctional biopolymers, represented by eumelanin, (597, 598). Eumelanogenesis involves the further transfor- pheomelanin, neuromelanin, and mixed melanin pigment mation of dopaquinone to leukodopachrome, followed by (323, 597, 598). Melanin biosynthesis can be initiated from a series of oxidoreduction reactions with production of either the hydroxylation of L-phenylalanine to L-tyrosine the intermediates dihydroxyindole (DHI) and DHI carbox- (nonobligatory step, operative in vivo) or directly from ylic acid (DHICA), that undergo polymerization to form FIG. 1. Synthesis of melanins. GSH, glutathione; Cys, cysteine. 1: Phenylalanine hydroxylation (by PH); 2: tyrosine hydroxylation (by either tyrosinase or TH); 3: DOPA oxidation (by tyrosinase or metal cations); 4: dopachrome tautomerization (by DCT/Tyrp2 or metal cations); 5a: DHICA oxidation (by Tyrp1 or peroxidase); 5b: DHI oxidation (by tyrosinase or peroxidase); a: hydrolysis of glutathionyldopa (by ␥-glutamyltranspeptidase); b: oxidation of cysteinyldopa (by peroxidase); c: intramolecular cyclization of cysteinyldopaquinone (may be facilitated by peroxidase); I: DOPA decarboxylation (by AAD); II: hydroxylation of dopamine (by DBH); III: methylation of norepinephrine (by PNMT). Physiol Rev • VOL 84 • OCTOBER 2004 • www.prv.org HORMONAL REGULATION OF MELANOGENESIS 1157 eumelanin (323, 573, 597). Pheomelanogenesis also starts slightly asymmetric singlet that generates a free radical with dopaquinone; this is conjugated to cysteine or gluta- signal at approximately g ϭ 2.004. The semiquinone units thione to yield cysteinyldopa and glutathionyldopa, for are also responsible for eumelanin actions as redox pig- further transformation into pheomelanin (323, 597, 598). ment with both reducing and oxidizing capabilities to- Mixed melanin contains both eu- and pheomelanin. wards oxygen radicals and other chemical redox systems L-DOPA generation of catecholamines requires its enzy- (126, 597, 598). Both eumelanin physical structure and matic decarboxylation, hydroxylation, and methylation to electrical properties are consistent with its behavior as an produce dopamine, norepinephrine, and epinephrine, re- amorphous semiconductor (210, 392, 544). Another inter- spectively (790). In vitro, all of these catecholamines can esting property of eu- and pheomelanin chemilumines- potentially convert into neuromelanin through several ox- cence is related to oxidative degradation of the melanin idation/reduction reactions (Fig. 1) (787); in vivo, only pigment (164, 658, 712). dopamine and cysteinyldopamine can serve as primary In contrast to eumelanin, pheomelanin has a back- precursors to the pigment (101, 151, 930). bone of benzothiazine units and exhibits a yellow to red- Melanin pigments have in common their arrangement dish-brown color and is alkali soluble (323, 597, 598). of several units linked by carbon-carbon bonds (C-C), but Pheomelanin is tightly bound to proteins, indicating that differ from each other in chemical composition, as well as in vivo it occurs as a chromoprotein (323, 597, 598), with structural and physical properties (323, 597, 598). Thus high variability in nitrogen and sulfur content (C/N and eumelanins are polymorphous nitrogenous biopolymers C/S ratios) (597, 598). Pheomelanin can also act as a (predominantly copolymers of DHI and DHICA), black to binding agent for drugs and chemicals (73, 458) and, like brown in color, insoluble in most solvents (597, 598), and eumelanin, contains semiquinones with their associated tightly associated with proteins through covalent bonds. paramagnetic properties, but it also holds additional Eumelanins behave like polyanions with the capability to semiquinonimine centers (688, 689). The resulting EPR reversibly bind cations, anions, and polyamines in reac- spectra of pheomelanins correspond therefore to a hyper- tions facilitated by their high carboxyl group content (323, fine structure with an unpaired electron localized near the 597, 598). A feature unique to eumelanin is a stable para- nucleus of 14N. These properties allow identification of magnetic state that results from its semiquinone units melanin type and quantification with EPR (Fig. 2) (443, (Fig. 2) (61, 126). Thus the electron paramagnetic reso- 586, 688, 689, 713, 739, 744, 745). Pheomelanins are pho- nance (EPR) spectrum of eumelanin corresponds to a tolabile, and its photolysis products include superoxide, FIG. 2. Electron paramagnetic reso- nance (EPR) analysis of melanin prod- ucts in follicular melanocytes from yel- low and black gerbils (top). Bottom, left: EPR spectrum of yellow hair showing hyperfine splitting similar to the spec- trum of cysteinylDOPA melanin (a syn- thetic model of pheomelanins). Asterisk indicates low field component of the splitting. Bottom, right: EPR signals of black hair and
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