Fig. 8.

Proposed mechanism of NH₃ transport by human Rhcg. The NH₃ secretory mechanism is shown, but transport appears to be bidirectional and reversible based upon the net NH₃ gradient. Acidic residues in the cytoplasmic vestibule result in NH₄⁺ concentration near the cytoplasmic opening of a 20-Å-long, narrow central pore. Change in the pK_a of the NH₄⁺/NH₃ buffer reaction results in increased local NH₃ concentrations. NH₃ can then transit the central pore, with weak stabilization mediated by 2 in-line histidine residues. A phenylalanine residue gates the extracellular vestibule and limits transit through Rhcg. Once in the extracellular vestibule, NH₃ is protonated, reforming NH₄⁺. Acidic residues, such as glutamate-166, in the extracellular vestibule provide weak interaction with NH₄⁺. A movie showing these critical amino acid residues in 3-dimensional format is provided in the supplementary materials (all supplementary material for this article is accessible on the journal Web site).