Research ArticleSkin Biology

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

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Sci. Signal.  06 Nov 2018:
Vol. 11, Issue 555, eaau7987
DOI: 10.1126/scisignal.aau7987

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A basic way to tan

Darker-skinned individuals have more melanin in their skin and a lower risk for skin cancer than fairer-skinned individuals. The production of melanin occurs in organelles called melanosomes and is regulated by melanosome pH. Zhou et al. found that cAMP generated by soluble adenylyl cyclase (sAC) resulted in decreases in melanosome pH and in the activity of tyrosinase, the rate-limiting enzyme in melanin synthesis. sAC deficiency or inhibitors increased melanosome pH and pigmentation in mice. These results define a mechanism of rapidly regulating melanin synthesis that could be exploited to reduce skin cancer risk for fair-skinned individuals.

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.

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