Figure 1.

Kinetic scheme for the electrogenic NaPi-IIa/b isoforms. Schematics represent the conformational states identified by previous functional analyses to show the occupancy of the proposed substrate-binding sites. The physiologically relevant cotransport cycle (clockwise, starting from state 0) involves a voltage-dependent reorientation of the unloaded carrier (state 0) to state 1 (assuming a hyperpolarized membrane potential), and movement of a single Na⁺ ion to the proposed Na1 site (state 2), followed by the cooperative interaction of a second Na⁺ ion before divalent P_i and a final Na⁺ ion, resulting in occupancy of the Na2-P_i-Na3 sites (state 4). A major translocation event then occurs (transition 4–5) and substrates can be released to the cytosol (transition 5–6). The last Na⁺ unbinding event (transition 6–0) effectively frees the empty carrier intrinsic charge to allow reorientation of the empty carrier to state 1 under the influence of a hyperpolarizing TM potential, in readiness for the next cycle. For the electroneutral NaPi-IIc, the empty carrier reorientation is voltage independent and no detectable charge displacement is associated with any of the partial reactions.