Regulation of pigmentation in human epidermal melanocytes by functional high-affinity beta-melanocyte-stimulating hormone/melanocortin-4 receptor signaling.
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 alpha-MSH and ACTH. In this context, it is noteworthy that beta-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 beta-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 beta-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 beta-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 beta-MSH/MC4-R cascade in human melanocyte biology, although the function and purpose of this signal in keratinocytes needs further elucidation.
Spencer
J D
JD
Department of Life Sciences, University of Bradford, Bradford, United Kingdom.
Schallreuter
K U
KU
D001665:Binding Sites; D002454:Cell Differentiation / Q000502:physiology; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism; D000078404:Epidermal Cells; D004817:Epidermis / Q000378:metabolism*; D006801:Humans; D015603:Keratinocytes / Q000378:metabolism; D008544:Melanocytes / Q000378:metabolism* / Q000502:physiology; D010456:Peptides, Cyclic / Q000494:pharmacology; D011485:Protein Binding; D044105:Receptor, Melanocortin, Type 4 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D012880:Skin Pigmentation / Q000235:genetics*; D019824:beta-MSH / Q000378:metabolism / Q000502:physiology*
C116941:HS014 cyclic peptide; D010456:Peptides, Cyclic; D044105:Receptor, Melanocortin, Type 4; D019824:beta-MSH; D000242:Cyclic AMP