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.

黑色素的产生增加皮肤色素沉着并降低患皮肤癌的风险。黑色素的产生取决于黑色素体的pH，黑色素体在皮肤较浅的人中比在皮肤较黑的人中更酸性。我们表明，通过增加细胞和体内黑素体的pH值，抑制可溶性腺苷酸环化酶（sAC）可以控制色素沉着。与经典的黑皮质素1受体（MC1R）依赖的cAMP途径（通过改变基因表达来控制色素沉着）不同，我们发现抑制sAC可以通过增加酪氨酸酶（黑色素合成中的限速酶）的活性来增加色素沉着。在碱性pH下。我们证明了sAC活性对人黑素细胞的pH和黑色素生成的影响取决于供体的皮肤颜色。最后的，