Sharpey‐Schafer Lecture: Gas channels

Abstract

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 (pHS) 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.

Relative CO2/NH3 selectivities of mammalian aquaporins 0–9

“…Thus it is possible that the approach in the earlier study was not sufficiently sensitive to detect the NH 3 permeability of AQP1. Moreover, at the high level of NH 3 /NH 4 ϩ used in the earlier study, oocytes exhibit large NH 3 /NH 4 ϩ -dependent conductances (24) and substantial decreases in pH i , neither of which appear at the [NH 3 /NH 4 ϩ ] o of 0.5 mM (42,44) used in the present study. Thus it is possible that the data obtained at high [NH 3 /NH 4 ϩ ] o values could reflect oocyte properties and thereby obscure the properties of heterologously expressed AQPs.…”

“…Previous work has shown that this aquaglyceroporin conducts water, glycerol, and urea (28). Moreover, as noted in the AQP1 section, other authors, working with 20 mM NH 3 / NH 4 ϩ , have reported that AQP3 conducts NH 3 (24). In the kidney, basolateral AQP3 contributes to water reabsorption along the entire collecting duct (12) and could contribute to urea reabsorption in the inner medullary collecting duct.…”

“…Conversely, exposing an oocyte to a solution containing NH 3 /NH 4 ϩ generates a transient fall in pH S as the weak base NH 3 enters the cell. All things being equal, the magnitude of the NH 3 -induced pH S is a semiquantitative index of NH 3 permeability.…”

The chemistry, physiology and pathology of pH in cancer

“…CO 2 has a high lipid : water partition coefficient, allowing it to cross the lipid bilayer freely. In addition (although not without controversy [18]), specialized gas channels such as aquaporins (AQP) have been demonstrated to increase membrane permeability to CO 2 [19]. Lactic acid, despite a much lower lipid : water partition coefficient, can cross the membrane as H þ -lactate, translocated by H þ -monocarboxylate transporters (MCT), including MCT1 and the hypoxia-inducible MCT4 [20] (according to the SoLute Carrier family naming convention, SLC16A1 and SLC16A3, respectively).…”

Alterations of red blood cell metabolome in overhydrated hereditary stomatocytosis

“…2 RhAG may function as an ammonium transporter and/or a gas channel. [3][4][5] When expressed in Xenopus laevis oocytes, the human wild-type RhAG induces a monovalent cation leak considerably enhanced when mutated RhAG transporters are expressed instead. 2 Among membrane abnormalities, OHSt RBCs display a sharp reduction or an absence of stomatin, 6 an integral RBC membrane protein.…”