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This Article Full Text Full Text (PDF) All Versions of this Article: 294/6/C1371    most recent 00398.2007v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Qu, Z. Articles by Hartzell, H. C. PubMed PubMed Citation Articles by Qu, Z. Articles by Hartzell, H. C.

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