The challenge of understanding ammonium homeostasis and the role of the Rh glycoproteins.

Rh glycoproteins belong to the superfamily of ammonium transporters, but until recent functional studies their functional role was unknown. This review focuses on the functional results obtained in our laboratory after the heterologous expression of RhAG (the erythroid Rh glycoprotein) and RhCG (an epithelial Rh glycoprotein). RhAG and RhCG were expressed in two different expression systems (HeLa cells and Xenopus laevis oocytes) that differed in their endogenous membrane permeabilities for NH3 and NH4+. To check if RhAG and RhCG are ammonium transporters, we measured intracellular pH changes in cells exposed to an ammonium-containing solution, and analyzed the ammonium-induced NH3 and NH4+ transmembrane fluxes in control versus transfected cells. We observed that RhAG and RhCG expression induced an enhancement of the ammonium-induced initial alkalinization (related to NH3 influx into the cell) and secondary acidification (related to NH4+ influx into the cell). Moreover, sub-millimolar ammonium concentrations induced inward currents in voltage-clamped RhAG- and in RhCG-expressing oocytes. Taken together, these results show not only that RhAG and RhCG are ammonium transporters, but also that they are promoting the transmembrane transport of NH3 and of NH4+. Data from our laboratory and from other groups raise several questions that are discussed.