TASK-2 is a background potassium channel opened by extracellular alkalinization that plays a role in bicarbonate reabsorption in kidney proximal tubule (Warth et al., 2004). Activation of TASK-2 is thought to require an alkalinization of the extracellular basolateral space secondary to bicarbonate efflux from the epithelial cells. An increase of TASK-2 from 24 to 50% of maximal activity corresponds to shifting pH from 7.4 to 8.0 (Niemeyer et al., 2007), and would require increasing bicarbonate to ~100 mM. Given this high concentration, we have looked for additional ways in which TASK-2 might be regulated. We report that TASK-2 is modulated by changes in intracellular pH that can be brought about by changing CO2 or sodium/bicarbonate cotransport. We have used whole cell patch-clamp to measure potassium currents mediated by TASK-2 expressed in HEK-293 cells. An intracellular alkalinization achieved by exposing the cells to a solution containing 10 mM ammonium-Cl, activated the currents 4.5 ± 0.6-fold (mean ± SEM, n=6, 0 mV, intra-/extracellular [K] 5/140 mM). Intracellular acidification by exposure to 5% CO2/33 mM Na-bicarbonate inhibited the current to 0.25 ± 0.1 (n=8) of its normalised control value. As reported in a separate communication in this Meeting, the intracellular pH-dependence of TASK-2 could also be directly verified using an acetate pH-clamping technique. To ascertain whether the type of changes in intracellular pH brought about by cotransporter-mediated bicarbonate fluxes could regulate TASK-2 we co-expressed it with proximal tubule NBCe1-A in HEK-293 cells. To resolve sodium/bicarbonate and potassium fluxes whole cell patch-clamp experiments were done at symmetrical [K] (110/110 mM). Cotransporter current was elicited by exposure to 5% CO2/33 mM Na-bicarbonate, and measured at 0 mV. Potassium current was measured at -70 mV with intracellular solutions devoid of sodium and nominally bicarbonate-free. Appearance of cotransporter-mediated inward current was always accompanied by TASK-2 current activation. This potassium current activation required cotransporter activity as it was inhibited by sodium removal or in the presence of 1 mM 4-4-dinitrostilbene-2, 2-disulphonic acid. As bath solutions containing CO2 and bicarbonate inhibit the current in the absence of cotransporter, we interpret these results as implying a functional interaction between TASK-2 and NBCe1-A, presumably through a bicarbonate influx-dependent intracellular alkalinization. Reversing the flow of sodium and bicarbonate had the opposite effect. NBCe1-A-dependent shifts in intracellular pH might contribute to regulating TASK-2 channel activity in the proximal tubule in vivo and to modulate bicarbonate reabsorption.