Milenkovic, Andrea and Brandl, Caroline and Milenkovic, Vladimir M. and Jendryke, Thomas and Sirianant, Lalida and Wanitchakool, Potchanart and Zimmermann, Stephanie and Reiff, Charlotte M. and Horling, Franziska and Schrewe, Heinrich and Schreiber, Rainer and Kunzelmann, Karl and Wetzel, Christian H. and Weber, Bernhard H. F. (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. ISSN 0027-8424,
Full text not available from this repository. (Request a copy)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.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | ESSENTIAL COMPONENT; BEST-DISEASE; MISSENSE MUTATIONS; KNOCKOUT MICE; ANION CURRENT; CHANNELS; GENE; IDENTIFICATION; PROTEIN; CONDUCTANCE; bestrophin 1; volume-regulated anion channel; induced pluripotent stem cell; retinal pigment epithelium; mouse sperm |
| Subjects: | 500 Science > 570 Life sciences 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Augenheilkunde Medicine > Lehrstuhl für Humangenetik Medicine > Lehrstuhl für Psychiatrie und Psychotherapie > Molekulare Neurowissenscahften Biology, Preclinical Medicine > Institut für Physiologie |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 15 Jul 2019 08:50 |
| Last Modified: | 15 Jul 2019 08:50 |
| URI: | https://pred.uni-regensburg.de/id/eprint/5498 |
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