Distinct cAMP signaling microdomains differentially regulate melanosomal pH and pigmentation.

Cyclic adenosine monophosphate (cAMP) signaling is a well-established regulator of melanin synthesis. Two distinct cAMP signaling pathways, the transmembrane adenylyl cyclase (tmAC) pathway, activated primarily by the melanocortin 1 receptor (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 demonstrate 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. Even though sAC loss of function in wild type human melanocytes stimulates melanin synthesis, sAC loss of function has no effect on melanin synthesis in MC1R non-functional human and mouse melanocytes or skin and hair melanin in (e/e) mice. Interestingly, activation of tmACs, which increases epidermal eumelanin synthesis in e/e mice, leads to enhanced production of eumelanin in sAC knockout mice relative to sAC wild type mice. Thus, MC1R- and sAC-dependent cAMP signaling pathways define distinct mechanisms that regulate melanosomal pH and pigmentation.