Bestrophin Cl- channels are highly permeable to HCO3-

Am J Physiol Cell Physiol. 2008 Jun;294(6):C1371-7. doi: 10.1152/ajpcell.00398.2007. Epub 2008 Apr 9.

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

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bestrophins
  • Bicarbonates / metabolism*
  • Cell Line
  • Cell Membrane Permeability*
  • Chloride Channels / genetics
  • Chloride Channels / metabolism*
  • Eye Proteins / genetics
  • Eye Proteins / metabolism*
  • Humans
  • Hydrogen-Ion Concentration
  • Membrane Potentials
  • Mice
  • Muscle Proteins / metabolism
  • Mutation
  • Sodium / metabolism
  • Transfection

Substances

  • BEST1 protein, human
  • BEST2 protein, human
  • BEST3 protein, human
  • BEST4 protein, human
  • Best2 protein, mouse
  • Bestrophins
  • Bicarbonates
  • Chloride Channels
  • Eye Proteins
  • Muscle Proteins
  • Sodium