Abstract
Intracellular organelles mediate complex cellular functions that often require ion transport across their membranes. Melanosomes are organelles responsible for the synthesis of the major mammalian pigment melanin. Defects in melanin synthesis result in pigmentation defects, visual deficits, and increased susceptibility to skin and eye cancers. Although genes encoding putative melanosomal ion transporters have been identified as key regulators of melanin synthesis, melanosome ion transport and its contribution to pigmentation remain poorly understood. Here we identify two-pore channel 2 (TPC2) as the first reported melanosomal cation conductance by directly patch-clamping skin and eye melanosomes. TPC2 has been implicated in human pigmentation and melanoma, but the molecular mechanism mediating this function was entirely unknown. We demonstrate that the vesicular signaling lipid phosphatidylinositol bisphosphate PI(3,5)P2 modulates TPC2 activity to control melanosomal membrane potential, pH, and regulate pigmentation.
Highlights
Intracellular organelles mediate complex cellular functions that often require ion transport across their membranes
We investigated if melanosomal channel activity could be regulated by PI(3,5)P2, an organellar phosphatidylinositol bisphosphate that is important in pigmentation[3] and activates the endolyosomal cation channels transient receptor potential mucolipin (TRPML)[4] and two-pore channels (TPCs)[5]
Because two-pore channel 2 (TPC2) has been previously implicated in pigmentation[12] and we find that it functions in melanosomes, we tested if TPC2 expression in melanocytes contributes to pigmentation
Summary
Intracellular organelles mediate complex cellular functions that often require ion transport across their membranes. Defects in melanin synthesis result in pigmentation defects, visual deficits, and increased susceptibility to skin and eye cancers. We identify two-pore channel 2 (TPC2) as the first reported melanosomal cation conductance by directly patch-clamping skin and eye melanosomes. We demonstrate that the vesicular signaling lipid phosphatidylinositol bisphosphate PI(3,5)P2 modulates TPC2 activity to control melanosomal membrane potential, pH, and regulate pigmentation. Using direct patch-clamp recordings from skin and eye melanosomes, we report the first melanosomal cation conductance mediated by two-pore channel 2 (TPC2). We show that the organellar signaling lipid PI(3,5)P2, an important regulator of pigmentation[3], activates a TPC2-mediated Na+-selective current in melanosomes. We found that TPC2 serves as a negative regulator of pigmentation by increasing melanosomal membrane potential and acidity to decrease cellular melanin content. In pigment cells, TPC2 mediates a PI(3,5)P2-activated melanosomal Na+ channel to regulate pigmentation by modulating the melanosome’s membrane voltage and pH
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