Mammalian pigmentation is regulated by a distinct cAMP-dependent mechanism that controls melanosome pH.

TitleMammalian pigmentation is regulated by a distinct cAMP-dependent mechanism that controls melanosome pH.
Publication TypeJournal Article
Year of Publication2018
AuthorsZhou D, Ota K, Nardin C, Feldman M, Widman A, Wind O, Simon A, Reilly M, Levin LR, Buck J, Wakamatsu K, Ito S, Zippin JH
JournalSci Signal
Volume11
Issue555
Date Published2018 Nov 06
ISSN1937-9145
Abstract

The production of melanin increases skin pigmentation and reduces the risk of skin cancer. Melanin production depends on the pH of melanosomes, which are more acidic in lighter-skinned than in darker-skinned people. We showed that inhibition of soluble adenylyl cyclase (sAC) controlled pigmentation by increasing the pH of melanosomes both in cells and in vivo. Distinct from the canonical melanocortin 1 receptor (MC1R)-dependent cAMP pathway that controls pigmentation by altering gene expression, we found that inhibition of sAC increased pigmentation by increasing the activity of tyrosinase, the rate-limiting enzyme in melanin synthesis, which is more active at basic pH. We demonstrated that the effect of sAC activity on pH and melanin production in human melanocytes depended on the skin color of the donor. Last, we identified sAC inhibitors as a new class of drugs that increase melanosome pH and pigmentation in vivo, suggesting that pharmacologic inhibition of this pathway may affect skin cancer risk or pigmentation conditions.

DOI10.1126/scisignal.aau7987
Alternate JournalSci Signal
PubMed ID30401788