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Journal Article

Aquaporin 4 as a NH3 channel.


Kaptan,  S.
Research Group of Computational Biomolecular Dynamics, MPI for Biophysical Chemistry, Max Planck Society;


de Groot,  B. L.
Research Group of Computational Biomolecular Dynamics, MPI for Biophysical Chemistry, Max Planck Society;

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Assentoft, M., Kaptan, S., Schneider, H. P., Deitmer, J. W., de Groot, B. L., & MacAulay, N. (2016). Aquaporin 4 as a NH3 channel. Journal of Biological Chemistry, 291(36), 19184-19195. doi:10.1074/jbc.M116.740217.

Cite as: http://hdl.handle.net/11858/00-001M-0000-002B-9B4C-5
Ammonia is a biologically potent molecule, and the regulation of ammonia levels in the mammalian body is, therefore, strictly controlled. The molecular paths of ammonia permeation across plasma membranes remain ill-defined, but the structural similarity of water and NH3 has pointed to the aquaporins as putative NH3-permeable pores. Accordingly, a range of aquaporins from mammals, plants, fungi, and protozoans demonstrates ammonia permeability. Aquaporin 4 (AQP4) is highly expressed at perivascular glia end-feet in the mammalian brain and may, with this prominent localization at the blood-brain-interface, participate in the exchange of ammonia, which is required to sustain the glutamate-glutamine cycle. Here we observe that AQP4-expressing Xenopus oocytes display a reflection coefficient <1 for NH4Cl at pH 8.0, at which pH an increased amount of the ammonia occurs in the form of NH3 Taken together with an NH4Cl-mediated intracellular alkalization (or lesser acidification) of AQP4-expressing oocytes, these data suggest that NH3 is able to permeate the pore of AQP4. Exposure to NH4Cl increased the membrane currents to a similar extent in uninjected oocytes and in oocytes expressing AQP4, indicating that the ionic NH4 (+) did not permeate AQP4. Molecular dynamics simulations revealed partial pore permeation events of NH3 but not of NH4 (+) and a reduced energy barrier for NH3 permeation through AQP4 compared with that of a cholesterol-containing lipid bilayer, suggesting AQP4 as a favored transmembrane route for NH3 Our data propose that AQP4 belongs to the growing list of NH3-permeable water channels.