The Journal of General Physiology
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Published online Aug 28 2006. doi:10.1085/jgp.200609581
The Rockefeller University Press, 0022-1295 $8.00
JGP, Volume 128, Number 3, 247-259
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ARTICLE

 Single Cl– Channels Activated by Ca2+ in Drosophila S2 Cells Are Mediated By Bestrophins



Li-Ting Chien, Zhi-Ren Zhang, 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 human bestrophin-1 (VMD2) are genetically linked to several forms of retinal degeneration but the underlying mechanisms are unknown. Bestrophin-1 (hBest1) has been proposed to be a Cl– channel involved in ion and fluid transport by the retinal pigment epithelium (RPE). To date, however, bestrophin currents have only been described in overexpression systems and not in any native cells. To test whether bestrophins function as Ca2+-activated Cl– (CaC) channels physiologically, we used interfering RNA (RNAi) in the Drosophila S2 cell line. S2 cells express four bestrophins (dbest1–4) and have an endogenous CaC current. The CaC current is abolished by several RNAi constructs to dbest1 and dbest2, but not dbest3 or dbest4. The endogenous CaC current was mimicked by expression of dbest1 in HEK cells, and the rectification and relative permeability of the current were altered by replacing F81 with cysteine. Single channel analysis of the S2 bestrophin currents revealed an ~2-pS single channel with fast gating kinetics and linear current–voltage relationship. A similar channel was observed in CHO cells transfected with dbest1, but no such channel was seen in S2 cells treated with RNAi to dbest1. This provides definitive evidence that bestrophins are components of native CaC channels at the plasma membrane.

Abbreviations used in this paper: BVMD, Best vitelliform macular dystrophy; CaC, Ca2+-activated Cl–; EOG, electrooculogram; hBest1, bestrophin-1; RPE, retinal pigment epithelium.


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