In the outward-open state (Ce), Na+ from the exterior medium gains access to the ion-binding site through the open extracellular funnel, where it replaces a bound proton. Na+ binding triggers the transition from the outward-open to the inward-open, substrate-bound conformation (CSi) via a substrate-occluded state (CSec). In the inward-open state, the cytoplasmic funnel widens and the extracellular funnel closes. A cytoplasmic proton releases the bound Na+ to the cell interior. Na+ release triggers the conformational change to the outward-open state via an occluded inward-open proton-bound conformation (CSic), and the cycle repeats. H5, 6 and 12 are color-coded. The 6-helix bundle (blue) performs a ∼7° rocking motion around an axis parallel to the dimer interface (light brown), which remains fixed in the membrane.