Bestrophin Cl− channels are highly permeable to HCO3−

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Abstract
Bestrophin-1 (Best1) is a Cl− channel that is linked to various retinopathies in both humans and dogs. Dysfunction of the Best1 Cl− channel has been proposed to cause retinopathy because of altered Cl− transport across the retinal pigment epithelium (RPE). In addition to Cl−, many Cl− channels also transport HCO3−. Because HCO3− is physiologically important in pH regulation and in fluid and ion transport across the RPE, we measured the permeability and conductance of bestrophins to HCO3− relative to Cl−. Four human bestrophin homologs (hBest1, hBest2, hBest3, and hBest4) and mouse Best2 (mBest2) were expressed in HEK cells, and the relative HCO3− permeability (PHCO3/PCl) and conductance (GHCO3/GCl) were determined. PHCO3/PCl was calculated from the change in reversal potential (Erev) produced by replacing extracellular Cl− with HCO3−. hBest1 was highly permeable to HCO3− (PHCO3/PCl = ∼0.44). hBest2, hBest4, and mBest2 had an even higher relative HCO3− permeability (PHCO3/PCl = 0.6–0.7). All four bestrophins had HCO3− conductances that were nearly the same as Cl− (GHCO3/GCl = 0.9–1.1). Extracellular Na+ did not affect the permeation of hBest1 to HCO3−. At physiological HCO3− concentration, HCO3− was also highly conductive. The hBest1 disease-causing mutations Y85H, R92C, and W93C abolished both Cl− and HCO3− currents equally. The V78C mutation changed PHCO3/PCl and GHCO3/GCl of mBest2 channels. These results raise the possibility that disease-causing mutations in hBest1 produce disease by altering HCO3− homeostasis as well as Cl− transport in the retina.