Department of Dermatology, NewYork-Presbyterian Hospital, Weill Cornell Medical College, New York, New York, USA.
Department of Biology, College of Arts and Sciences, University of Alabama at Birmingham, Birmingham, Alabama, USA.
J Invest Dermatol. 2023 Oct;143(10):2019-2029.e3. doi: 10.1016/j.jid.2023.04.011. Epub 2023 May 2.
cAMP signaling is a well-established regulator of melanin synthesis. Two distinct cAMP signaling pathways-the transmembrane adenylyl cyclase pathway, activated primarily by the MC1R, and the soluble adenylyl cyclase (sAC) pathway-affect melanin synthesis. The sAC pathway affects melanin synthesis by regulating melanosomal pH, and the MC1R pathway affects melanin synthesis by regulating gene expression and post-translational modifications. However, whether MC1R genotype affects melanosomal pH is poorly understood. We now report that loss of function MC1R does not affect melanosomal pH. Thus, sAC signaling appears to be the only cAMP signaling pathway that regulates melanosomal pH. We also addressed whether MC1R genotype affects sAC-dependent regulation of melanin synthesis. Although sAC loss of function in wild-type human melanocytes stimulates melanin synthesis, sAC loss of function has no effect on melanin synthesis in MC1R nonfunctional human and mouse melanocytes or skin and hair melanin in e/e mice. Interestingly, activation of transmembrane adenylyl cyclases, which increases epidermal eumelanin synthesis in e/e mice, leads to enhanced production of eumelanin in sAC-knockout mice relative to that in sAC wild-type mice. Thus, MC1R- and sAC-dependent cAMP signaling pathways define distinct mechanisms that regulate melanosomal pH and pigmentation.
cAMP 信号转导是黑色素合成的一个成熟的调节剂。两种不同的 cAMP 信号通路——跨膜腺苷酸环化酶通路，主要由 MC1R 激活，和可溶性腺苷酸环化酶（sAC）通路——影响黑色素合成。sAC 通路通过调节黑素小体 pH 来影响黑色素合成，而 MC1R 通路通过调节基因表达和翻译后修饰来影响黑色素合成。然而，MC1R 基因型是否影响黑素小体 pH 尚不清楚。我们现在报告说，功能丧失型 MC1R 并不影响黑素小体 pH。因此，sAC 信号似乎是唯一调节黑素小体 pH 的 cAMP 信号通路。我们还研究了 MC1R 基因型是否影响 sAC 依赖性的黑色素合成调节。尽管野生型人黑素细胞中 sAC 的功能丧失会刺激黑色素合成，但 sAC 功能丧失对 MC1R 无功能的人和鼠黑素细胞或 e/e 小鼠的皮肤和毛发黑色素的黑色素合成没有影响。有趣的是，跨膜腺苷酸环化酶的激活增加了 e/e 小鼠表皮真黑色素的合成，导致 sAC 敲除小鼠相对于 sAC 野生型小鼠的真黑色素生成增加。因此，MC1R 和 sAC 依赖性 cAMP 信号通路定义了调节黑素小体 pH 和色素沉着的不同机制。
