(A) Hydrogen ion produced by anaerobic metabolism within the cell must first be converted to carbon dioxide to facilitate diffusion across the lipid bilayer. This reaction with bicarbonate is catalysed by cytoplasmic CA. Once carbon dioxide has diffused into the extracellular space, CA activity in the boundary layer may regenerate protons, maintaining the carbon dioxide diffusion gradient. (B) The NHE is one method by which protons may be actively pumped from the cell. Alternatively, bicarbonate in the extracellular space (regenerated from carbon dioxide hydration with CA catalysis) may be imported into the cell via the chloride–bicarbonate AE. This bicarbonate may recombine with a proton in the cytoplasm to undertake further shuttling across the membrane. This recycling of bicarbonate with net proton extrusion is known as a Jacobs–Stewart cycle. The AE has recently been shown to bind CAII on its intracellular surface