Figure 6.

Schematic representation of the cascade of ion channels and transporters with a role in melanogenesis. Melanosome acidification, needed in the early stages of melanosome maturation, is accomplished by V-ATPases. To increase the melanosomal pH, which allows for melanogenesis, the H⁺ protons are returned to the cytoplasm through sodium–proton exchangers, namely NHE-3 and NHE-7. OCA2 is a chloride (Cl^-) channel that reduces proton import into melanosomes, neutralizing the luminal pH and activating the pH-sensitive TYR enzyme. SLC45A2 has also been proposed to act as proton/glucose exporter, respectively. The excess of Na⁺ needs to be cycled out of the melanosomes, which involves SLC24A5. The exchanger activity of SLC24A5 also provides a link between cytosolic and melanosomal Ca²⁺. TPC2 was found to function as an Na⁺-selective channel, providing the negative regulation of melanogenesis by increasing melanosomal membrane potential and acidity, possibly by providing a cation counterflux to enhance the H⁺ transport by V-ATPases. The counterbalance of Ca²⁺ influx can be accomplished by TRPML3, to the neutralization of melanosomal pH. Cystinosin is a cystine/H⁺ symporter that controls the efflux of cystine; its ability to efflux protons along with cystine also renders it as having a role in the control of melanosomal pH. Moreover, the coordinated activities of both cystinosin and SLC7A11 may determine the levels of melanosomal cysteine, therefore influencing the eumelanin/pheomelanin ratio. Cys: cysteine; CySS: cystine; Glu: glutamate; NHE: sodium hydrogen exchanger; OCA2: oculocutaneous albinism 2 protein; SLC(7A11/24A5/45A2): solute carrier family 7/24/45, member 11/5/2; TPC2: two pore segment channel 2; TRPML3: transient receptor potential cation channel, mucolipin subfamily, member 3; V-ATPase: vacuolar ATPase.