Loss of vision caused by an alkaline shift in the pH-dependence of the corneal H+/OH−-conducting membrane protein Slc4a11

SLC4A11 is the only member of the solute carrier 4 family of membrane transport proteins that transports H+ (or its thermodynamic equivalent OH−) rather than bicarbonate or carbonate. Mutations in SLC4A11 result in the loss of the fluid pumping function of cells that line the posterior of the cornea (corneal endothelial cells), resulting in corneal swelling and vision loss (corneal dystrophy). SLC4A11-mediated H+/OH− conductance is exquisitely sensitive to both intracellular and extracellular pH (pHi and pHe), being activated by a rise in either, and could help to regulate the pH of both compartments to maintain transport processes. One mutation in SLC4A11 ‘Arg125His’ that causes corneal dystrophy appears to render SLC4A11 inactive under physiological conditions. We expressed wild-type and R125H mutant SLC4A11 in Xenopus oocytes. We measured the membrane conductance of those cells under voltage clamp and monitored pHi with a H+-selective microelectrode as we caused pHi and/or pHe to rise. We found that, at fixed pHe = 8.50, the pKi that describes the pHi-dependence of mutant SLC4A11 activity is alkaline shifted (greater than 7.60, n = 8) compared to wild-type (7.04 +/− 0.01, n = 7), explaining the loss of function. However, as we increased pHe to 10.00, mutant pKi rose to a value (7.06 +/− 0.08, n = 6) close to that of wild-type SLC4A11. These observations indicate that the molecular defect in SLC4A11/R125H lies with the pHe-dependence of pKi (presumably the ability of pHe to cause the appropriate long-range, transmembrane conformational-changes in SLC4A11) and suggest that the defect in the SLC4A11/R125H mutant may be amenable to pharmacological correction.