%0 Journal Article
%T Two-pore channel 2 is required for soluble adenylyl cyclase-dependent regulation of melanosomal pH and melanin synthesis.
%A Zhou D
%A Eraslan Z
%A Miller D
%A Taylor I
%A You J
%A Grondin SJ
%A Vega M
%A Manga P
%A Goff PS
%A Sviderskaya EV
%A Gross SS
%A Chen Q
%A Zippin JH
%J Pigment Cell Melanoma Res
%V 0
%N 0
%D 2024 Jun 6
%M 38844435
%F 4.159
%R 10.1111/pcmr.13177
%X 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.