Abstract：
Melanosomal pH is important for the synthesis of melanin as the rate-limiting enzyme, tyrosinase, is very pH-sensitive. The soluble adenylyl cyclase (sAC) signaling pathway was recently identified as a regulator of melanosomal pH in melanocytes; however, the melanosomal proteins critical for sAC-dependent regulation of melanosomal pH were undefined. We now systematically examine four well-characterized melanosomal membrane proteins to determine whether any of them are required for sAC-dependent regulation of melanosomal pH. We find that OA1, OCA2, and SLC45A2 are dispensable for sAC-dependent regulation of melanosomal pH. In contrast, TPC2 activity is required for sAC-dependent regulation of melanosomal pH and melanin synthesis. In addition, activation of TPC2 by NAADP-AM rescues melanosomal pH alkalinization and reduces melanin synthesis following pharmacologic or genetic inhibition of sAC signaling. These studies establish TPC2 as a critical melanosomal protein for sAC-dependent regulation of melanosomal pH and pigmentation.
摘要：
黑色素的pH值作为限速酶对黑色素的合成很重要,酪氨酸酶,对pH非常敏感。可溶性腺苷酸环化酶（sAC）信号通路最近被确定为黑素细胞中黑色素体pH的调节剂；然而，对sAC依赖性黑色素体pH调节至关重要的黑色素体蛋白未定义.现在，我们系统地检查了四种特征明确的黑素瘤膜蛋白，以确定sAC依赖性调节黑素瘤pH值是否需要它们中的任何一种。我们发现OA1，OCA2和SLC45A2对于sAC依赖性的黑色素细胞pH调节是不必要的。相比之下,TPC2活性是sAC依赖性调节黑色素体pH和黑色素合成所必需的。此外,NAADP-AM对TPC2的激活可以挽救黑色素体pH碱化，并减少sAC信号的药理学或遗传学抑制后的黑色素合成。这些研究将TPC2确立为用于sAC依赖性调节黑色素体pH和色素沉着的关键黑色素体蛋白。
