ArticleProceedings of the National Academy of Sciences of the United States of America2017
TPC2 polymorphisms associated with a hair pigmentation phenotype in humans result in gain of channel function by independent mechanisms.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 51 papers, 1 of them a synthesis that pooled it.
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Who cites it
51 citing papers in PubMed, 1 synthesis or guideline pooled it, 71 citations in OpenAlex.
- The protein interaction networks of mucolipins and two-pore channels.Biochimica et biophysica acta. Molecular cell research · 2019Pooled it
- Inhibition of endolysosomal two-pore channel 2 (TPC2) induces osteoblast differentiation and matrix mineralization while targeting autophagy.Journal of endocrinological investigation · 2026Article
- Allosteric switching of CaThe EMBO journal · 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
- NAADP elicits two-pore channel currents by lifting Lsm12-mediated inhibition of PI(3,5)PbioRxiv : the preprint server for biology · 2026Article
- Polymethoxyflavones from Kaempferia parviflora stimulate melanogenesis by blocking the TPC2 channel.Scientific reports · 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
- TPC2: From Blond Hair to Melanoma?Cancers · 2024Review
- Rab7a is an enhancer of TPC2 activity regulating melanoma progression through modulation of the GSK3β/β-Catenin/MITF-axis.Nature communications · 2024Article
- Two-pore channel 2 is required for soluble adenylyl cyclase-dependent regulation of melanosomal pH and melanin synthesis.Pigment cell & melanoma research · 2024Article
- Structural basis for inhibition of the lysosomal two-pore channel TPC2 by a small molecule antagonist.Structure (London, England : 1993) · 2024Article
- The ion channels of endomembranes.Physiological reviews · 2024Review
- Population Structure and Genomic Characterisation of the Ashanti Dwarf Pig of Ghana.Animals : an open access journal from MDPI · 2024Article
- Two-pore channels regulate endomembrane tension to enable remodeling and resolution of phagolysosomes.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- Identification of Candidate Genes for Red-Eyed (Albinism) Domestic Guppies Using Genomic and Transcriptomic Analyses.International journal of molecular sciences · 2024Article
- Missing Heritability in Albinism: Deep Characterization of a Hungarian Albinism Cohort Raises the Possibility of the Digenic Genetic Background of the Disease.International journal of molecular sciences · 2024Article
- Two-pore channel regulators - Who is in control?Frontiers in physiology · 2024Review
- A Comprehensive Review of Mammalian Pigmentation: Paving the Way for Innovative Hair Colour-Changing Cosmetics.Biology · 2023Review
Corrections and comments
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Authors and funding
14 authors at 4 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Two-pore channels (TPCs) are endolysosomal cation channels. Two members exist in humans, TPC1 and TPC2. Functional roles associated with the ubiquitously expressed TPCs include VEGF-induced neoangiogenesis, LDL-cholesterol trafficking and degradation, physical endurance under fasting conditions, autophagy regulation, the acrosome reaction in sperm, cancer cell migration, and intracellular trafficking of pathogens such as Ebola virus or bacterial toxins (e.g., cholera toxin). In a genome-wide association study for variants associated with human pigmentation characteristics two coding variants of TPC2, rs35264875 (encoding M484L) and rs3829241 (encoding G734E), have been found to be associated with a shift from brown to blond hair color. In two recent follow-up studies a role for TPC2 in pigmentation has been further confirmed. However, these human polymorphic variants have not been functionally characterized until now. The development of endolysosomal patch-clamp techniques has made it possible to investigate directly ion channel activities and characteristics in isolated endolysosomal organelles. We applied this technique here to scrutinize channel characteristics of the polymorphic TPC2 variants in direct comparison with WT. We found that both polymorphisms lead to a gain of channel function by independent mechanisms. We next conducted a clinical study with more than 100 blond- and brown/black-haired individuals. We performed a genotype/phenotype analysis and subsequently isolated fibroblasts from WT and polymorphic variant carriers for endolysosomal patch-clamp experimentation to confirm key in vitro findings.
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