Melanocortin Receptor Ligands: New Horizons for Skin Biology and Clinical Dermatology

Department of Dermatology and Ludwig Boltzmann Institute for Cell Biology and Immunobiology of the Skin, University of Münster, Germany.
Journal of Investigative Dermatology (Impact Factor: 6.37). 08/2006; 126(9):1966-1975. DOI: 10.1038/sj.jid.5700421

ABSTRACT The melanocortin (MC) system is probably the best characterized neuropeptide network of the skin. Most cutaneous cell types express MC receptors (MC-Rs) and synthesize MCs, such as -melanocyte-stimulating hormone (-MSH), that act in autocrine and paracrine fashion. In human skin cells, activation of adenylate cyclase by MCs occurs at 10-6–10-9 M doses of the ligand, but effects are induced in some cell types at subnanomolar concentrations. In addition to the pigmentary action of MCs on epidermal melanocytes, the hair follicle is a source and target for MCs. MCs regulate lipogenesis in sebocytes expressing both MC-1R and MC-5R. In adipocytes, lipid metabolism is modulated by agouti signalling protein, a natural MC-1R/MC-4R antagonist. The anti-inflammatory activity of -MSH includes immunomodulatory effects on several resident skin cells and antifibrogenic effects mediated via MC-1R expressed by dermal fibroblasts. In human mast cells, -MSH appears to be proinflammatory due to histamine release. -MSH exhibits cytoprotective activity against UVB-induced apoptosis and DNA damage, a finding that helps explain the increased risk of cutaneous melanoma in individuals with loss of function MC-1R mutations. These findings should improve our understanding of skin physiology and pathophysiology and may offer novel strategies with MCs as future therapeutics for skin diseases.Abbreviations: AGRP, agouti-related peptide; AP, agouti protein; ASP, Agouti signalling protein; GRK, G protein-coupled receptor kinase; LPS, lipopolysaccharide; MC, melanocortin; Mc-r, (murine) melanocortin receptor; MC-R, (human) melanocortin receptor; MSH, melanocyte-stimulating hormone; POMC, proopiomelanocortin; RHC, red hair and fair skin; TGF-, transforming growth factor-; TM, transmembrane; TNF-, tumor necrosis factor-

  • [Show abstract] [Hide abstract]
    ABSTRACT: The application of afamelanotide, an α-melanocyte stimulating hormone agonistic analogue to protoporphyria, a disease with absolute sunlight-intolerance is discussed. The clinics, genetics and existing therapies of protoporphyria are described. The physiological receptor-mediated intracellular signaling of α-melanocyte stimulating hormone and effects of receptor variants are outlined. The pharmacological action of afamelanotide and the rationale behind its application in protoporphyria are given. The results of several Phase II and III and safety issues are discussed. The trial results were significant, although the effects were not very large in absolute terms, and the risk-safety profile is favorable today. Based on the high compliance rate and the excellent consistency in clinical effectiveness during six years of compassionate use program in Switzerland, we expect afamelanotide and analogues to become a prospective therapeutic tool. Moreover, we hope that dosage forms suitable for children will be developed in future, as children and adolescents suffer most in protoporphyria.
    Expert Review of Clinical Pharmacology 12/2014; DOI:10.1586/17512433.2014.956089
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The human skin is not only a target for the protective actions of melatonin, but also a site of melatonin synthesis and metabolism, suggesting an important role for a local melatoninergic system in protection against ultraviolet radiation (UVR) induced damages. While melatonin exerts many effects on cell physiology and tissue homeostasis via membrane bound melatonin receptors, the strong protective effects of melatonin against the UVR-induced skin damage including DNA repair/protection seen at its high (pharmocological) concentrations indicate that these are mainly mediated through receptor-independent mechanisms or perhaps through activation of putative melatonin nuclear receptors. The destructive effects of the UVR are significantly counteracted or modulated by melatonin in the context of a complex intracutaneous melatoninergic anti-oxidative system with UVR-enhanced or UVR-independent melatonin metabolites. Therefore, endogenous intracutaneous melatonin production, together with topically-applied exogenous melatonin or metabolites would be expected to represent one of the most potent anti-oxidative defense systems against the UV-induced damage to the skin. In summary, we propose that melatonin can be exploited therapeutically as a protective agent or as a survival factor with anti-genotoxic properties or as a "guardian" of the genome and cellular integrity with clinical applications in UVR-induced pathology that includes carcinogenesis and skin aging.
    International Journal of Molecular Sciences 10/2014; 15(10):17705-17732. DOI:10.3390/ijms151017705 · 2.34 Impact Factor
  • Journal of Investigative Dermatology 04/2015; 135(4):929-31. DOI:10.1038/jid.2015.16 · 6.37 Impact Factor