NHE1 Na/H exchange cycle with inactivation. The exchange cycle moves one Na inwardly and one proton outwardly (states 1 to 4) when the exchanger inactivation domain is disengaged and has three protons occluded within it. Exchangers transition to inactivated states with release of regulatory protons preferentially when exchangers are open to the outside and have bound a proton, as well as when anionic lipids such as PIP₂ are depleted from the cytoplasmic monolayer. Inactive states are stabilized by dephosphorylation and loss of protons from regulatory sites. Na binding from either membrane side may favor return to the active states, together with phosphorylation and increased anionic lipid content of the cytoplasmic monolayer.