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

Alzbeta      Hulikova; Adrian      L. Harris; Richard      D. Vaughan-Jones; Pawel      Swietach

Abstract

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 (pHi) regulation aims to balance this system of diffusion-reaction-transport processes at a favourable steady-state pHi. The ability of cells to regulate pHi 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 pHi regulation. A particularly important feature of tumour pHi 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 pHi regulation in a specific type of cancer.

Keywords: pHi regulation, membrane transport, CO2/HCO3-buffer, carbonic anhydrase, cancer, acid-extrusion, hypoxia, spheroid, acid-retention, extracellular H+ diffusion