Sharpey-Schafer Lecture Gas channels

The traditional dogma has been that all gases diffuse through all membranes simply by dissolving in the lipid phase of the membrane. Although this mechanism may explain how most gases move through most membranes, it is now clear that some membranes have no demonstrable gas permeability, and that at least two families of membrane proteins, the aquaporins (AQPs) and the Rhesus (Rh) proteins, can each serve as pathways for the diffusion of both CO₂ and NH₃. The knockout of RhCG in the renal collecting duct leads to the predicted consequences in acid-base physiology, providing a clear-cut role for at least one gas channel in the normal physiology of mammals. In our laboratory, we have found that surface-pH (pH(S)) transients provide a sensitive approach for detecting CO₂ and NH₃ movement across the cell membranes of Xenopus oocytes. Using this approach, we have found that each tested AQP and Rh protein has its own characteristic CO₂/NH₃ permeability ratio, which provides the first demonstration of gas selectivity by a channel. Our preliminary AQP1 data suggest that all the NH₃ and less than half of the CO₂ move along with H₂O through the four monomeric aquapores. The majority of CO₂ takes an alternative route through AQP1, possibly the central pore at the four-fold axis of symmetry. Preliminary data with two Rh proteins, bacterial AmtB and human erythroid RhAG, suggest a similar story, with all the NH₃ moving through the three monomeric NH₃ pores and the CO₂ taking a separate route, perhaps the central pore at the three-fold axis of symmetry. The movement of different gases via different pathways is likely to underlie the gas selectivity that these channels exhibit.