Modulation of the Two-pore Domain Acid-sensitive K+ Channel TASK-2 (KCNK5) by Changes in Cell Volume

Abstract

The molecular identity of K+ channels involved in Ehrlich cell volume regulation is unknown. A background K+ conductance is activated by cell swelling and is also modulated by extracellular pH. These characteristics are most similar to those of newly emerging TASK (TWIK-related acid-sensitive K+ channels)-type of two pore-domain K+ channels. mTASK-2, but not TASK-1 or -3, is present in Ehrlich cells and mouse kidney tissue from where the full coding sequences were obtained. Heterologous expression of mTASK-2 cDNA in HEK-293 cells generated K+ currents in the absence intracellular Ca2+. Exposure to hypotonicity enhanced mTASK-2 currents and osmotic cell shrinkage led to inhibition. This occurred without altering voltage dependence and with only slight decrease in pK a in hypotonicity but no change in hypertonicity. Replacement with other cations yields a permselectivity sequence for mTASK-2 of K+ > Rb+ ≫ Cs+ > NH+ > Na+ ≒ Li+, similar to that for the native conductance (IK, vol). Clofilium, a quaternary ammonium blocker of IK, vol, blocked the mTASK-2-mediated K+ current with an IC50 of 25 μM. The presence of mTASK-2 in Ehrlich cells, its functional similarities with IK, vol, and its modulation by changes in cell volume suggest that this two-pore domain K+ channel participates in the regulatory volume decrease phenomenon.