Acid-extrusion from Tissue: The Interplay Between Membrane Transporters and pH Buffers

The acid-base balance of cells is related to the concentration of free H+ ions. These are highly reactive, and their intracellular concentration must be regulated to avoid detrimental effects to the cell. H+ ion dynamics are influenced by binding to chelator substances ('buffering'), and by the production, diffusion and membrane-transport of free H+ ions or of the H+-bound chelators. Intracellular pH (pH(i)) regulation aims to balance this system of diffusion-reaction-transport processes at a favourable steady-state pH(i). The ability of cells to regulate pH(i) may set a limit to tissue growth and can be subject to selection pressures. Cancer cells have been postulated to respond favourably to such selection pressures by evolving a better means of pH(i) regulation. A particularly important feature of tumour pH(i) regulation is acid-extrusion, which involves H+-extrusion and HCO3--uptake by membrane-bound transporter-proteins. Extracellular CO2/HCO3- buffer facilitates these membrane-transport processes. As a mobile pH-buffer, CO2/HCO3- protects the extracellular space from excessive acidification that could otherwise inhibit further acid-extrusion. CO2/HCO3- also provides substrate for HCO3--transporters. However, the inherently slow reaction kinetics of CO2/HCO3- can be rate-limiting for acid-extrusion. To circumvent this, cells can express extracellular-facing carbonic anhydrase enzymes to accelerate the attainment of equilibrium between CO2, HCO3- and H+. The acid-extrusion apparatus has been proposed as a target for anti-cancer therapy. The major targets include H+ pumps, Na+/H+ exchangers and carbonic anhydrases. The effectiveness of such therapy will depend on the correct identification of rate-limiting steps in pH(i) regulation in a specific type of cancer.