An intracellular anion channel critical for pigmentation

Bellono, Nicholas W.; Escobar, Iliana E.; Lefkovith, Ariel; Marks, Michael S.; Oancea, Elena

doi:10.7554/elife.04543

Cited by 110 publications

(152 citation statements)

References 40 publications

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“…Several other ion channels and transporters involved in human pigmentation are present in the melanosome-limiting membrane. The recently described OCA2-mediated Cl − channel regulates melanin synthesis in part through melanosome pH (7,9). The melanosome-localized K + -dependent Na + /Ca 2+ exchanger, SLC24A5, regulates pigmentation, potentially through pH changes (2, 34).…”

Section: Discussionmentioning

confidence: 99%

“…This OCA2 loop was previously used to add other tags without affecting the protein trafficking and function (26). Providing OCA2 functions in chloride transport, we used the nonconductive V443I pore mutant to avoid any change MELOPS expression might cause on melanosomal pH (9). The feasibility of using MELOPS to measure melanosomal pH was tested by expressing it in MNT-1 cells and incubating the cells in buffers with pH values ranging from 4.5 to 6.5 in the presence of ionophores (27).…”

Section: Tpc2 Regulates Melanosome Luminal Phmentioning

confidence: 99%

“…Importantly, the activity of tyrosinase, the rate-limiting enzyme in melanin synthesis, is greatly reduced at acidic pH. Melanosomal pH, rather than tyrosinase expression level, has been shown to regulate tyrosinase activity and the amount of melanin produced in melanocytes from different skin types (2,(7)(8)(9). Melanosomes from melanocytes of fair-skinned individuals are significantly more acidic and display low tyrosinase activity, whereas melanosomes in dark skin melanocytes are less acidic or neutral and present higher levels of tyrosinase activity (8,10).…”

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confidence: 99%

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TPC2 controls pigmentation by regulating melanosome pH and size

Ambrosio

Boyle

Aradi

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

109

103

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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.melanosome | pigmentation | two-pore channel 2 | organelle pH | membrane traffic

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Section: Discussionmentioning

confidence: 99%

Section: Tpc2 Regulates Melanosome Luminal Phmentioning

confidence: 99%

mentioning

confidence: 99%

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TPC2 controls pigmentation by regulating melanosome pH and size

Ambrosio

Boyle

Aradi

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

109

103

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“…It has recently been shown to assist in anion transport increasing chloride conductance from the melanosome [49] . The R305W (rs1800401), R419Q (rs1800407), and V443I (rs121918166) coding polymorphisms are associated with eye colour [50,51] and R419Q is associated with increased BCC risk [43] .…”

Section: Oca2: the Major Gene For Eye Colour And Albinism Type IImentioning

confidence: 99%

Skin Pigmentation Genetics for the Clinic

Ainger

Jagirdar²,

Lee³

et al. 2017

Dermatology

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Human pigmentation characteristics play an important role in the effects of sun exposure, skin cancer induction and disease outcomes. Several of the genes most important for this diversity are involved in the regulation and distribution of melanin pigmentation or enzymes involved in melanogenesis itself within the melanocyte cell present in the skin, hair and eyes. The single nucleotide polymorphisms and extended haplotypes within or surrounding these genes have been identified as risk factors for skin cancer, in particular, melanoma. These same polymorphisms have been under selective pressure leading towards lighter pigmentation in Europeans in the last 5,000-20,000 years that have driven the increase in frequency in modern populations. Although pigmentation is a polygenic trait, due to interactive and quantitative gene effects, strong phenotypic associations are readily apparent for these major genes. However, predictive value and utility are increased when considering gene polymorphism interactions. In melanoma, an increased penetrance is found in cases when pigmentation gene risk alleles such as MC1R variants are coincident with mutation of higher-risk melanoma genes including CDKN2A, CDK4 and MITF E318K, demonstrating an interface between the pathways for pigmentation, naevogenesis and melanoma. The clinical phenotypes associated with germline changes in pigmentation and naevogenic genes must be understood by clinicians, and will be of increasing relevance to dermatologists, as genomics is incorporated into the delivery of personalised medicine.

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“…For example, the albinism-causing OCA2 proteins are reported to encode a Cl- channel in melanosomes that are important for pigmentation [63]. …”

Section: The Endocytic Compartmentsmentioning

confidence: 99%

Organellar channels and transporters

Martinoia

Szabó

2015

Cell Calcium

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Decades of intensive research has led to the discovery of most plasma membrane ion channels and transporters and the characterization of their physiological functions. In contrast, although over 80% of transport processes occur inside the cells, the ion flux mechanisms across intracellular membranes (the endoplasmic reticulum, Golgi apparatus, endosomes, lysosomes, mitochondria, chloroplasts, and vacuoles) are difficult to investigate and remain poorly understood. Recent technical advances in super-resolution microscopy, organellar electrophysiology, organelle-targeted fluorescence imaging, and organelle proteomics have pushed a large step forward in the research of intracellular ion transport. Many new organellar channels are molecularly identified and electrophysiologically characterized. Additionally, molecular identification of many of these ion channels/transporters has made it possible to study their physiological functions by genetic and pharmacological means. For example, organellar channels have been shown to regulate important cellular processes such as programmed cell death and photosynthesis, and are involved in many different pathologies. This Special Issue (SI) on Organellar Channels and Transporters aims to provide a forum to discuss the recent advances and to define the standard and open questions in this exciting and rapidly-developing field. Along this line, a new Gordon Research Conference dedicated to the multidisciplinary study of intracellular membrane transport proteins will be launched this coming summer.

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An intracellular anion channel critical for pigmentation

Cited by 110 publications

References 40 publications

TPC2 controls pigmentation by regulating melanosome pH and size

TPC2 controls pigmentation by regulating melanosome pH and size

Skin Pigmentation Genetics for the Clinic

Organellar channels and transporters

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