ArticleProceedings of the National Academy of Sciences of the United States of America2016
TPC2 controls pigmentation by regulating melanosome pH and size.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 87 papers.
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Who cites it
87 citing papers in PubMed, 127 citations in OpenAlex.
- Identifying causal genetic variants for high-altitude adaptation through blood eQTL analysis in plateau populations.Communications biology · 2026Article
- TPC1-dependent control of endosomal pH and transferrin uptake determines cellular iron status.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- Decoding Hyperpigmentation from Biological Mechanisms to Actives with Clinically Proven Topical Efficacy: A Narrative Review.Dermatology and therapy · 2026Review
- TPC2 regulates proteomic remodeling, bioenergetic phenotypes, and mitochondrial stress adaptation in melanoma.Saudi pharmaceutical journal : SPJ : the official publication of the Saudi Pharmaceutical Society · 2026Article
- NAADP elicits two-pore channel currents by lifting Lsm12-mediated inhibition of PI(3,5)PbioRxiv : the preprint server for biology · 2026Article
- Lysosome-related organelles orchestrate guanine crystal formation in pigment cells.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- STIM1-Mitofusin2 interactions tether mitochondria and melanosome contacts that promote melanosome maturation.Nature communications · 2026Article
- Review
- pH variations enable guanine crystal formation within iridosomes.Nature chemical biology · 2026Article
- Polymethoxyflavones from Kaempferia parviflora stimulate melanogenesis by blocking the TPC2 channel.Scientific reports · 2025Article
- Chromosome-scale Genomes Show Rapid Diversification and Ancient Gene Flow Among Bear Species.Genome biology and evolution · 2025Article
- The Two-Pore Channel 2 in Human Physiology and Diseases: Functional Characterisation and Pharmacology.International journal of molecular sciences · 2025Review
- Lysosomal Ion Channels and Transporters: Recent Findings, Therapeutic Potential, and Technical Approaches.Bioelectricity · 2025Review
- A patient with TPCN2-related hypopigmentation and ocular phenotype.European journal of human genetics : EJHG · 2025Article
- On the Origin of Information Dynamics in Early Life.Life (Basel, Switzerland) · 2025Article
- Reprogramming the melanoma and immunosuppressive myeloid cells with esomeprazole-loaded PLGA nanoparticles.iScience · 2025Article
- Chemigenetic Ca2+ indicators report elevated Ca2+ levels in endothelial Weibel-Palade bodies.PloS one · 2025Article
- Specialised features of melanosomes in health and disease in the retinal pigment epithelium.Frontiers in cell and developmental biology · 2025Review
- Insights into lysosome-related organelle biogenesis: melanosome as a model organelle.Frontiers in cell and developmental biology · 2025Article
- TPC2: From Blond Hair to Melanoma?Cancers · 2024Review
27 more citing papers are in PubMed but not listed here.
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Authors and funding
5 authors at 1 institution in 1 country.
Funding
Abstract
Melanin is responsible for pigmentation of skin and hair and is synthesized in a specialized organelle, the melanosome, in melanocytes. A genome-wide association study revealed that the two pore segment channel 2 (TPCN2) gene is strongly linked to pigmentation variations. TPCN2 encodes the two-pore channel 2 (TPC2) protein, a cation channel. Nevertheless, how TPC2 regulates pigmentation remains unknown. Here, we show that TPC2 is expressed in melanocytes and localizes to the melanosome-limiting membrane and, to a lesser extent, to endolysosomal compartments by confocal fluorescence and immunogold electron microscopy. Immunomagnetic isolation of TPC2-containing organelles confirmed its coresidence with melanosomal markers. TPCN2 knockout by means of clustered regularly interspaced short palindromic repeat/CRISPR-associated 9 gene editing elicited a dramatic increase in pigment content in MNT-1 melanocytic cells. This effect was rescued by transient expression of TPC2-GFP. Consistently, siRNA-mediated knockdown of TPC2 also caused a substantial increase in melanin content in both MNT-1 cells and primary human melanocytes. Using a newly developed genetically encoded pH sensor targeted to melanosomes, we determined that the melanosome lumen in TPC2-KO MNT-1 cells and primary melanocytes subjected to TPC2 knockdown is less acidic than in control cells. Fluorescence and electron microscopy analysis revealed that TPC2-KO MNT-1 cells have significantly larger melanosomes than control cells, but the number of organelles is unchanged. TPC2 likely regulates melanosomes pH and size by mediating Ca(2+) release from the organelle, which is decreased in TPC2-KO MNT-1 cells, as determined with the Ca(2+) sensor tyrosinase-GCaMP6. Thus, our data show that TPC2 regulates pigmentation through two fundamental determinants of melanosome function: pH and size.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.