Ion transport in pigmentation

Abstract

Skin melanocytes and ocular pigment cells contain specialized organelles called melanosomes, which are responsible for the synthesis of melanin, the major pigment in mammals. Defects in the complex mechanisms involved in melanin synthesis and regulation result in vision and pigmentation deficits, impaired development of the visual system, and increased susceptibility to skin and eye cancers. Ion transport across cellular membranes is critical for many biological processes, including pigmentation, but the molecular mechanisms by which it regulates melanin synthesis, storage, and transfer are not understood. In this review we first discuss ion channels and transporters that function at the plasma membrane of melanocytes; in the second part we consider ion transport across the membrane of intracellular organelles, with emphasis on melanosomes. We discuss recently characterized lysosomal and endosomal ion channels and transporters associated with pigmentation phenotypes. We then review the evidence for melanosomal channels and transporters critical for pigmentation, discussing potential molecular mechanisms mediating their function. The studies investigating ion transport in pigmentation physiology open new avenues for future research and could reveal novel molecular mechanisms underlying melanogenesis.

Keywords: Ion channel; Melanocyte; Melanosome; Pigmentation; Transporter.

Figure 1. Melanocyte plasma membrane ion channels with potential roles in pigmentation

Schematic representation of ionic currents through TRP channels (TRPM1, TRPM7 and TRPA1) and mediated by the interaction of the ER protein complex STIM with the plasma membrane ORAI1, that regulate pigmentation. Pigmentation could be modulated by changes in membrane voltage (+V_m), shown to occur in response to TRPA1 activation. Alternatively, increased cytosolic Ca²⁺ mediated by influx through these channels, could lead to Ca²⁺ transport into melanosomes, modulate pigmentation by activating PKCβ to increase tyrosinase (TYR) activity, regulate organelle interaction events, or trigger melanin transfer.

Figure 2. Putative melanosomal ion transport proteins

(Left) Schematic representation of endolysosomal ion channels with potential role in pigmentation. TRPML and TPC mediate cation efflux from melanosomes and mutations or SNPs in these channels suggest that they might also function in melanosomes. The ClC-7 exchanger regulates the luminal pH of endolysosomes, mediates anion transport, and its expression regulates pigmentation. V-ATPases contribute to proton influx into melanothomes and pH regulation. (Right) Schematic representation of melanosomal ion channels with role in pigmentation. Putative melanosomal transporters OCA2, SLC45A2 and SLC24A5 are mutated in types of human oculocutaneous albinism (OCA), but little is known about how they function. Here we show predicted functions based on homology to other transporters with characterized functions. The putative melanosomal G protein coupled receptor OA1 could activate an ion channel, thereby regulating ion transport activity. V-ATPase and ATP7A contribute to acidification of the lumen and copper (Cu²⁺) transport, respectively. These ion channels and transporters could modulate pigmentation by directly or indirectly regulating the enzymatic activity of tyrosinase (TYR), which is critical for melanin synthesis. Bidirectional arrows represent anti- or co-transporters and unidirectional arrows represent uniporters or pumps.