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Regulation of Pigmentation in Human Epidermal Melanocytes by Functional High-Affinity β-Melanocyte-Stimulating Hormone/Melanocortin-4 Receptor Signaling

Clinical and Experimental Dermatology/Department of Life Sciences, University of Bradford, Bradford BD7 1DP, United Kingdom, and Institute for Pigmentary Disorders in Association with the Ernst Moritz Arndt University Greifswald, Germany, and University of Bradford

Address all correspondence and requests for reprints to: Professor Karin U. Schallreuter, Clinical and Experimental Dermatology, University of Bradford, Bradford, United Kingdom, BD7 1DP. E-mail: k.schallreuter{at}bradford.ac.uk.

To date, the principal receptor considered to regulate human pigmentation is the melanocortin-1 receptor (MC1-R) via induction of the cAMP/protein kinase A pathway by the melanocortins -MSH and ACTH. In this context, it is noteworthy that β-MSH can also induce melanogenesis, although it has a low affinity for the MC1-R, whereas the preferred receptor for this melanocortin is the MC4-R. Because β-MSH is present in the epidermal compartment, it was of interest to ascertain whether functioning MC4-Rs are present in human epidermal keratinocytes and melanocytes. Our results provide evidence that the MC4-R is expressed in situ and in vitro throughout the human epidermis at the mRNA and protein level using RT-PCR, Western blotting, and double immunofluorescence staining. Moreover, radioligand binding studies yielded high-affinity receptors for β-MSH on epidermal melanocytes (3600 receptors per cell), undifferentiated keratinocytes (7200 receptors per cell), and differentiated keratinocytes (72,700 receptors per cell), indicating that MC4-R expression correlates with epidermal differentiation. Importantly, increased melanogenesis after stimulation of the β-MSH/cAMP/microphthalmia-associated transcription factor/tyrosinase cascade proved the functionality of this signal in melanocytes, which was attenuated in the presence of the specific MC4-R antagonist HS014. In summary, our results imply an important role for the β-MSH/MC4-R cascade in human melanocyte biology, although the function and purpose of this signal in keratinocytes needs further elucidation.