Under isotonic conditions, empty NKCC1 binds in the order: one Na+, one Cl−, one K+ and a second Cl−. After translocation, NKCC1 releases in the same order: the Na+, the first Cl−, the K+ and the second Cl−.Then, the cotransporter translocates empty and the cycle repeats. Under hypertonicity, partial reactions occur with the transporter reversing inside prior to unloading the second Cl− and outside prior to unloading the Na+. As a result, these partial cycles exchange external K+ and Cl− for internal K+ and Cl−, i.e. K+/K+ and Cl−/Cl− exchanges. Externally loaded ions are represented in black, internally loaded ions are represented in red.