The Journal of General Physiology
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Published online
doi:10.1085/jgp.200709795
The Journal of General Physiology, Vol. 130, No. 5, 513-524
The Rockefeller University Press, 0022-1295 $30.00
© Chien et al.
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ARTICLE

 Drosophila Bestrophin-1 Chloride Current Is Dually Regulated by Calcium and Cell Volume



Li-Ting Chien and H. Criss Hartzell

Department of Cell Biology and Center for Neurodegenerative Disease, Emory University School of Medicine, Atlanta, GA 30322

Correspondence to Criss Hartzell: criss.hartzell{at}emory.edu

Mutations in the human bestrophin-1 (hBest1) gene are responsible for Best vitelliform macular dystrophy, however the mechanisms leading to retinal degeneration have not yet been determined because the function of the bestrophin protein is not fully understood. Bestrophins have been proposed to comprise a new family of Cl– channels that are activated by Ca2+. While the regulation of bestrophin currents has focused on intracellular Ca2+, little is known about other pathways/mechanisms that may also regulate bestrophin currents. Here we show that Cl– currents in Drosophila S2 cells, that we have previously shown are mediated by bestrophins, are dually regulated by Ca2+ and cell volume. The bestrophin Cl– currents were activated in a dose-dependent manner by osmotic pressure differences between the internal and external solutions. The increase in the current was accompanied by cell swelling. The volume-regulated Cl– current was abolished by treating cells with each of four different RNAi constructs that reduced dBest1 expression. The volume-regulated current was rescued by transfecting with dBest1. Furthermore, cells not expressing dBest1 were severely depressed in their ability to regulate their cell volume. Volume regulation and Ca2+ regulation can occur independently of one another: the volume-regulated current was activated in the complete absence of Ca2+ and the Ca2+-activated current was activated independently of alterations in cell volume. These two pathways of bestrophin channel activation can interact; intracellular Ca2+ potentiates the magnitude of the current activated by changes in cell volume. We conclude that in addition to being regulated by intracellular Ca2+, Drosophila bestrophins are also novel members of the volume-regulated anion channel (VRAC) family that are necessary for cell volume homeostasis.

Abbreviations used in this paper: CaCC, calcium-activated Cl channel; dBest, Drosophila bestrophin; hBest, human bestrophin; RPE, retinal pigment epithelium; RVD, regulatory volume decrease; VRAC, volume-regulated anion channel.


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