Bestrophin Cl- channels are highly permeable to HCO3-

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 (P-HCO3/P-Cl) and conductance (G(HCO3)/G(Cl)) were determined. P-HCO3/P-Cl was calculated from the change in reversal potential (E-rev) produced by replacing extracellular Cl- with HCO3-. hBest1 was highly permeable to HCO3- (P-HCO3/P-Cl = similar to 0.44). hBest2, hBest4, and mBest2 had an even higher relative HCO3- permeability (P-HCO3/P-Cl = 0.6-0.7). All four bestrophins had HCO3- conductances that were nearly the same as Cl- (G(HCO3)/G(Cl) = 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 P-HCO3/P-Cl and G(HCO3)/G(Cl) 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.