Ca2+-activated Cl- channels (CaCCs) participate in a variety of important physiological processes such as transepithelial transport, olfactory and taste transduction, neuronal and cardiac excitability, fototransduction and fertility. These Cl- channels also play a key role in diseases such as cystic fibrosis, and polycystic kidney disease. Although epithelial CaCCs have been studied for more than two decades, their molecular identity and physiological role remain uncertain. Whereas most

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... e molecules have failed to fulfill CaCC requisites, proteins of the bestrophin family have been demonstrated to induce a Ca2+-acitivated Cl- conductance in expression systems. The properties of this conductance resembled those of Ca2+-activated Cl- currents (IClCa) in native tissues. Bestrophin 1 (best1), the gene product of the vitelliform macular dystrophy type 2 (VMD2), is expressed in the retinal pigment epithelium (RPE) where it is thought to underlie the Cl- conductance that controls retinal homeostasis. Mutations in best1 gene cause the so-called Best disease, a genetic form of retinal macular dystrophy. There is not yet a consensus as to whether Best disease is caused by Cl- channel dysfunction, partly because mbest1 knockout mice (best1-/-) have no ocular pathology and normal Cl- currents can be recorded from the RPE. It has also been shown that best1 regulates voltage-gated Ca2+ channels in the RPE. The precise cellular role of bestrophins therefore remains an unresolved question. Most importantly, bestrophins remain to be demonstrated to generate IClCa in tissues other than the RPE. The present work demonstrates that best1 is also expressed in other epithelial tissues, such as airways, kidney and colon where it enables Ca2+-activated Cl- secretion. Endogenous IClCa coincide with endogenous expression of best1 in murine and human epithelial cells, whereas IClCa is absent in epithelial tissues lacking best1 expression. Furthermore, IClCa is shown to be activated by ATP in HEK293 cells overexpressing hbest1. Ussing [...]