β‐Endorphin/β MSH – two neglected melanotropins?

Abstract

POMC processing in human melanocytes has been widely documented, and the α‐MSH/MC1R/cAMP cascade has been implicated in the control of pigmentation. Only very recently, a role of β‐endorphin, one cleavage product of β‐LPH, has been demonstrated to influence melanocyte growth, dendricity and melanin biosynthesis via the µ‐opiate receptor. However, much earlier, it was shown that β‐MSH, the other cleavage product of β‐LPH, controls melanogenesis and melanin transfer in amphibians. To date, a specific receptor for β‐MSH has not been identified. Earlier POMC processing has been found in melanosomes. Therefore, an MC1R‐independent role of α‐MSH was postulated and demonstrated in control of 6‐tetrahydrobiopterin (6BH4)‐inhibited tyrosinase. Utilizing the depigmentation disorder vitiligo, we were now able to follow the fate of epidermal POMC processing in the presence of mM levels of hydrogen peroxide (H2O2). In vitiligo epidermal PC2 and 7B2 protein expression is increased, whereas α‐MSH, β‐MSH and β‐endorphin are significantly decreased. Analysis of the peptide sequences revealed in all three cases H2O2 oxidation targets such as methionine and tryptophan yielding significant structural alterations. Moreover, we have identified a new function of β‐MSH due to its capacity to bind the important cofactor 6BH4 as well as its isomer 7BH4. Hence, we propose for the first time that β‐MSH can control both the supply of l‐tyrosine from l‐phenylalanine via phenylalanine hydroxylase and l‐Dopa synthesis via tyrosinase hydroxylase in melanocytes and keratinocytes. Therefore, both melanogenesis and catecholamine synthesis could be regulated by this peptide.