{Reference Type}: Journal Article
{Title}: Two-pore channel 2 is required for soluble adenylyl cyclase-dependent regulation of melanosomal pH and melanin synthesis.
{Author}: Zhou D;Eraslan Z;Miller D;Taylor I;You J;Grondin SJ;Vega M;Manga P;Goff PS;Sviderskaya EV;Gross SS;Chen Q;Zippin JH;
{Journal}: Pigment Cell Melanoma Res
{Volume}: 0
{Issue}: 0
{Year}: 2024 Jun 6
{Factor}: 4.159
{DOI}: 10.1111/pcmr.13177
{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.