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  Bestrophin 1 is indispensable for volume regulation in human retinal pigment epithelium cells

Milenkovic, A., Brandl, C., Milenkovic, V. M., Jendryke, T., Sirianant, L., Wanitchakool, P., et al. (2015). Bestrophin 1 is indispensable for volume regulation in human retinal pigment epithelium cells. Proceedings of the National Academy of Sciences of the United States of America, 112(20), E2630-E2639. doi:10.1073/pnas.1418840112.

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Item Permalink: http://hdl.handle.net/11858/00-001M-0000-0028-92F9-3 Version Permalink: http://hdl.handle.net/11858/00-001M-0000-0028-9300-B
Genre: Journal Article

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 Creators:
Milenkovic, Andrea, Author
Brandl, Caroline, Author
Milenkovic, Vladimir M. , Author
Jendryke, Thomas , Author
Sirianant, Lalida , Author
Wanitchakool, Potchanart , Author
Zimmermann, Stephanie , Author
Reiff, Charlotte M. , Author
Horling, Franziska , Author
Schrewe, Heinrich1, Author              
Schreiber, Rainer, Author
Kunzelmann, Karl, Author
Wetzel, Christian H. , Author
Weber, Bernhard H. F. , Author
Affiliations:
1Dept. of Developmental Genetics (Head: Bernhard G. Herrmann), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1433548              

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Free keywords: bestrophin 1, volume-regulated anion channel, induced pluripotent stem cell, retinal pigment epithelium, mouse sperm
 Abstract: In response to cell swelling, volume-regulated anion channels (VRACs) participate in a process known as regulatory volume decrease (RVD). Only recently, first insight into the molecular identity of mammalian VRACs was obtained by the discovery of the leucine-rich repeats containing 8A (LRRC8A) gene. Here, we show that bestrophin 1 (BEST1) but not LRRC8A is crucial for volume regulation in human retinal pigment epithelium (RPE) cells. Whole-cell patch-clamp recordings in RPE derived from human-induced pluripotent stem cells (hiPSC) exhibit an outwardly rectifying chloride current with characteristic functional properties of VRACs. This current is severely reduced in hiPSC-RPE cells derived from macular dystrophy patients with pathologic BEST1 mutations. Disruption of the orthologous mouse gene (Best1−/−) does not result in obvious retinal pathology but leads to a severe subfertility phenotype in agreement with minor endogenous expression of Best1 in murine RPE but highly abundant expression in mouse testis. Sperm from Best1−/− mice showed reduced motility and abnormal sperm morphology, indicating an inability in RVD. Together, our data suggest that the molecular identity of VRACs is more complex—that is, instead of a single ubiquitous channel, VRACs could be formed by cell type- or tissue-specific subunit composition. Our findings provide the basis to further examine VRAC diversity in normal and diseased cell physiology, which is key to exploring novel therapeutic approaches in VRAC-associated pathologies.

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Language(s): eng - English
 Dates: 2015-05-042015-05-19
 Publication Status: Published in print
 Pages: -
 Publishing info: -
 Table of Contents: -
 Rev. Type: -
 Identifiers: DOI: 10.1073/pnas.1418840112
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Title: Proceedings of the National Academy of Sciences of the United States of America
  Other : Proc. Natl. Acad. Sci. USA
Source Genre: Journal
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Publ. Info: Washington, DC : National Academy of Sciences
Pages: - Volume / Issue: 112 (20) Sequence Number: - Start / End Page: E2630 - E2639 Identifier: ISSN: 0027-8424
CoNE: https://pure.mpg.de/cone/journals/resource/954925427230