title: A melanosomal two-pore sodium channel regulates pigmentation.
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.
authors.affiliation: Department of Molecular Pharmacology, Physiology, and Biotechnology, Brown University, Providence, RI 02912, USA.
authors.forename: Nicholas W
authors.initials: NW
authors.lastname: Bellono
authors.affiliation: Department of Molecular Pharmacology, Physiology, and Biotechnology, Brown University, Providence, RI 02912, USA.
authors.forename: Iliana E
authors.initials: IE
authors.lastname: Escobar
authors.affiliation: Department of Molecular Pharmacology, Physiology, and Biotechnology, Brown University, Providence, RI 02912, USA.
authors.forename: Elena
authors.initials: E
authors.lastname: Oancea
mesh_terms: D000818:Animals; D015220:Calcium Channels / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D005123:Eye / Q000166:cytology* / Q000378:metabolism; D006863:Hydrogen-Ion Concentration; D008544:Melanocytes / Q000166:cytology / Q000378:metabolism; D020460:Melanosomes / Q000378:metabolism* / Q000502:physiology; D008564:Membrane Potentials; D051379:Mice; D018408:Patch-Clamp Techniques; D019269:Phosphatidylinositol 4,5-Diphosphate / Q000378:metabolism; D010858:Pigmentation; D012867:Skin / Q000166:cytology* / Q000378:metabolism
chemical_list: D015220:Calcium Channels; D019269:Phosphatidylinositol 4,5-Diphosphate; C546785:TPCN2 protein, mouse