CHARACTERIZATION OF ACTH PEPTIDES IN HUMAN SKIN AND THEIR ACTIVATION OF THE MELANOCORTIN-1 RECEPTOR

alpha-Melanocyte-stimulating hormone (alpha-MSH) is a proopiomelanocor tin (POMC) derived peptide, which is produced in the pituitary and at other sites including the skin. It has numerous effects and in the ski n has a pigmentary action through the activation of the melanocortin-1 (MC-1) receptor, which is expressed by melanocytes. Recent evidence s uggests that the related POMC peptides such as adrenocorticotrophin (A CTH), which is the precursor of alpha-MSH, is also an agonist at the M C-1 receptor. By using immunocytochemistry, we confirmed the presence of alpha-MSH in human skin where staining was evident in keratinocytes and especially strong in melanocytes and possibly Langerhans cells. A CTH was also present and tended to show the strongest reaction in diff erentiated keratinocytes. Immunostaining was also observed for the pro hormone convertases, PC1 and PC2, which are involved in the formation of ACTH and its cleavage to alpha-MSH, respectively. The amounts of im munoreactive ACTH exceeded those of alpha-MSH. Using HPLC we identifie d for the first time the presence of ACTH1-39, ACTH1-17, ACTH1-10, ace tylated ACTH1-10, alpha-MSH, and desacetyl alpha-MSH in epidermis and in cultured keratinocytes. The ability of these peptides to activate t he human MC-1 receptor was examined in HEK 293 cells that had been tra nsfected with the receptor. All peptides increased adenylate cyclase i n these cells with the following order of potency: ACTH1-17 > alpha-MS H > ACTH1-39 > desacetyl alpha-MSH > acetylated ACTH1-10 > ACTH1-10. A CTH1-17 also increased the dendricity and melanin content of cultured human melanocytes indicating that the peptide was able to activate MC- 1 receptors when present in their normal location. However, as found w ith alpha-MSH, not all cultures were responsive and, as we ha ve previ ously suggested, we suspect that this was the result of changes at the MC-1 receptor. Nevertheless, it would appear that ACTH peptides can s erve as natural ligands of the MC-1 receptor on human melanocytes and their presence in the skin suggests that, together with alpha-MSH, the y may have a role in the regulation of human melanocytes.