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MEMBRANE TRANSPORTERS, ION CHANNELS, AND PUMPS

Bestrophin Cl^– channels are highly permeable to HCO₃^–

¹Department of Cell Biology and Center for Neurodegenerative Disease, Emory University School of Medicine, Atlanta, Georgia; and ²Department of Physiology, Qingdao University School of Medicine, Qingdao, Shandong, China

Submitted 31 August 2007 ; accepted in final form 1 April 2008

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 = 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.

bicarbonate transport; pH; retinal pigment epithelium; retinopathy

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