A sufficiently high intracellular pH (Phi) is permissive for cell survival, growth, function and proliferation. High metabolic production of H+ ions is compensated for by acid extrusion on ion transport proteins such as Na/H exchange (NHE) and Na-HCO3 co-transport (NBC). This helps to regularise pHi in individual cells. In addition, H+-ion cross-talk between adjacent cells helps to co-ordinate pHi throughout the tissue. The talk will contrast two different pHi-co-ordination strategies. One is common in poorly vascularised developing tumours and relies on the activity of exofacial carbonic anhyrase enzymes, notably HIF-activated CAIX, which facilitates the venting of cellular CO2. The other, which is common in the heart, is the buffer-shuttling of acid via histidyl dipeptides (HDPs) and CO2/HCO3– between cells, through gap junctions (predominantly Cx43 channels in the myocardium). Extracellular CAIX operates in concert with membrane HCO3- influx on NBC. CAIX up-regulation in hypoxic zones is associated with down-regulation of cytoplasmic CAs such as CAII. NBCs are constitutively expressed at high basal activity in a wide range of tumour cell-lines, unlike NHE1 that can be at either high or low functional level. By facilitating CO2 diffusion out of cells, CAIX raises pHi and reduces pHo, producing the functional hall-mark of aggressive cancer. Down regulation of CAIX activity, either by genetic manipulation or by pharmacological inhibition, typically results in a more acidic core pHi in 3-D spheroid growths (eg. RT112; HCT116), a more heterogeneous spatial pHi distribution, and a more alkaline pH in the restricted extracellular spaces. Gap-junctional channels tend to be repressed in developing tumours, but they are commonly expressed in most healthy tissues. Cx43 channels in the myocardium mediate high passive H+ flux whenever [H+]i differences are presented across junctional regions. High H+-flux is achieved by reversible binding to intrinsic HDPs (carnsoine, anserine, homocarnosine) that are present in cytoplasm (~15mM), and which readily permeate the junction. HCO3 anion flux through the channels also enhances cell-cell H+ transmission. The H+ and HCO3- flux is gated by moderate [H+]i and high [H+]i which increases and reduces Cx43 channel permeability respectively. These are acute channel-gating phenomena, also observed for Cx43 channels stably transfected into Hela or N2A cell-pairs. Because buffer permeation of Cx43 channels is high, so is cell-cell H+ ion transmission. The system provides for spatial H+ communication and permits slow H+ diffusive equilibration of pHi in tissue, resulting in a pHi syncitium that regularises cell function. H+-gating of cell-cell H+ flux (autoregulation) is absent when the cytoplasmic tail of Cx43 sub-units is truncated. The talk will compare the kinetics and spatial outreach of CAIX and Cx43 mediated pHi control, highlighting the potential advantages of each mechanism.