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Proc Natl Acad Sci U S A
2015 May 19;11220:E2630-9. doi: 10.1073/pnas.1418840112.
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Bestrophin 1 is indispensable for volume regulation in human retinal pigment epithelium cells.
Milenkovic A
,
Brandl C
,
Milenkovic VM
,
Jendryke T
,
Sirianant L
,
Wanitchakool P
,
Zimmermann S
,
Reiff CM
,
Horling F
,
Schrewe H
,
Schreiber R
,
Kunzelmann K
,
Wetzel CH
,
Weber BH
.
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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.
Ackerman,
Hypotonicity activates a native chloride current in Xenopus oocytes.
1994, Pubmed,
Xenbase
Ackerman,
Hypotonicity activates a native chloride current in Xenopus oocytes.
1994,
Pubmed
,
Xenbase
Anderson,
Cation regulation of anion current activated by cell swelling in two types of human epithelial cancer cells.
1995,
Pubmed
Brandl,
In-depth characterisation of Retinal Pigment Epithelium (RPE) cells derived from human induced pluripotent stem cells (hiPSC).
2014,
Pubmed
Chien,
Single Cl- channels activated by Ca2+ in Drosophila S2 cells are mediated by bestrophins.
2006,
Pubmed
Chien,
Rescue of volume-regulated anion current by bestrophin mutants with altered charge selectivity.
2008,
Pubmed
Cocquet,
Deficiency in the multicopy Sycp3-like X-linked genes Slx and Slxl1 causes major defects in spermatid differentiation.
2010,
Pubmed
Cooper,
The epididymis, cytoplasmic droplets and male fertility.
2011,
Pubmed
Cross,
Electro-oculography in Best's macular dystrophy.
1974,
Pubmed
Darszon,
Sperm channel diversity and functional multiplicity.
2006,
Pubmed
De La Fuente,
Small-molecule screen identifies inhibitors of a human intestinal calcium-activated chloride channel.
2008,
Pubmed
Fischmeister,
Volume sensitivity of the bestrophin family of chloride channels.
2005,
Pubmed
Hartzell,
Molecular physiology of bestrophins: multifunctional membrane proteins linked to best disease and other retinopathies.
2008,
Pubmed
Johnson,
Differential effects of Best disease causing missense mutations on bestrophin-1 trafficking.
2013,
Pubmed
Joseph,
Epididymal hypo-osmolality induces abnormal sperm morphology and function in the estrogen receptor alpha knockout mouse.
2010,
Pubmed
Kirichok,
Rediscovering sperm ion channels with the patch-clamp technique.
2011,
Pubmed
Krämer,
Cloning and characterization of the murine Vmd2 RFP-TM gene family.
2004,
Pubmed
Kunzelmann,
Calcium-dependent chloride conductance in epithelia: is there a contribution by Bestrophin?
2007,
Pubmed
Kunzelmann,
Role of the Ca2+ -activated Cl- channels bestrophin and anoctamin in epithelial cells.
2011,
Pubmed
Lang,
Functional significance of cell volume regulatory mechanisms.
1998,
Pubmed
Lee,
Channel-mediated tonic GABA release from glia.
2010,
Pubmed
Marmorstein,
The light peak of the electroretinogram is dependent on voltage-gated calcium channels and antagonized by bestrophin (best-1).
2006,
Pubmed
Marquardt,
Mutations in a novel gene, VMD2, encoding a protein of unknown properties cause juvenile-onset vitelliform macular dystrophy (Best's disease).
1998,
Pubmed
Martins,
Anoctamin 6 is an essential component of the outwardly rectifying chloride channel.
2011,
Pubmed
Milenkovic,
Disease-associated missense mutations in bestrophin-1 affect cellular trafficking and anion conductance.
2011,
Pubmed
Mohler,
Long-term evaluation of patients with Best's vitelliform dystrophy.
1981,
Pubmed
Morin,
Failure of P-glycoprotein (MDR1) expressed in Xenopus oocytes to produce swelling-activated chloride channel activity.
1995,
Pubmed
,
Xenbase
Navarro,
ATP-activated P2X2 current in mouse spermatozoa.
2011,
Pubmed
Neussert,
The presence of bestrophin-1 modulates the Ca2+ recruitment from Ca2+ stores in the ER.
2010,
Pubmed
Nilius,
Properties of volume-regulated anion channels in mammalian cells.
1997,
Pubmed
O'Shaughnessy,
Identification of developmentally regulated genes in the somatic cells of the mouse testis using serial analysis of gene expression.
2003,
Pubmed
Petrukhin,
Identification of the gene responsible for Best macular dystrophy.
1998,
Pubmed
Qiu,
SWELL1, a plasma membrane protein, is an essential component of volume-regulated anion channel.
2014,
Pubmed
Ren,
A sperm ion channel required for sperm motility and male fertility.
2001,
Pubmed
Singh,
iPS cell modeling of Best disease: insights into the pathophysiology of an inherited macular degeneration.
2013,
Pubmed
Stotz,
Anion-sensitive fluorophore identifies the Drosophila swell-activated chloride channel in a genome-wide RNA interference screen.
2012,
Pubmed
Stöhr,
Three novel human VMD2-like genes are members of the evolutionary highly conserved RFP-TM family.
2002,
Pubmed
Sun,
The vitelliform macular dystrophy protein defines a new family of chloride channels.
2002,
Pubmed
Voets,
Reduced intracellular ionic strength as the initial trigger for activation of endothelial volume-regulated anion channels.
1999,
Pubmed
Voss,
Identification of LRRC8 heteromers as an essential component of the volume-regulated anion channel VRAC.
2014,
Pubmed
Woo,
TREK-1 and Best1 channels mediate fast and slow glutamate release in astrocytes upon GPCR activation.
2012,
Pubmed
Xu,
Cystic fibrosis transmembrane conductance regulator is vital to sperm fertilizing capacity and male fertility.
2007,
Pubmed
Yeung,
Sperm volume regulation: maturational changes in fertile and infertile transgenic mice and association with kinematics and tail angulation.
2002,
Pubmed
Yeung,
Infertile spermatozoa of c-ros tyrosine kinase receptor knockout mice show flagellar angulation and maturational defects in cell volume regulatory mechanisms.
1999,
Pubmed
Yeung,
Receptor tyrosine kinase c-ros knockout mice as a model for the study of epididymal regulation of sperm function.
1998,
Pubmed
Zeng,
Deletion of the Slo3 gene abolishes alkalization-activated K+ current in mouse spermatozoa.
2011,
Pubmed
