Selectivity and interactions of Ba2+ and Cs+ with wild-type and mutant TASK1 K+ channels expressed in Xenopus oocytes

The acid-sensitive K+ channel, TASK1 is a member of the K+-selective tandem-pore domain (K2P) channel family. Like many of the K2P channels, TASK1 is relatively insensitive to conventional channel blockers such as Ba2+. In this paper we report the impact of mutating the pore-neighbouring histidine residues, which are involved in pH sensing, on the sensitivity to blockade by Ba2+ and Cs+; additionally we compare the selectivity of these channels to extracellular K+, Na+ and Rb+. H98D and H98N mutants showed reduced selectivity for K+ over both Na+ and Rb+, and significant permeation of Rb+. This enhanced permeability must reflect changes in the structure or flexibility of the selectivity filter. Blockade by Ba2+ and Cs+ was voltage-dependent, indicating that both ions block within the pore. In 100 mm K+, the K-D at 0 mV for Ba2+ was 36 +/- 10 mm (n = 6), whilst for Cs+ it was 20 +/- 6.0 mm (n = 5). H98D was more sensitive to Ba2+ than the wild-type (WT); in addition, the site at which Ba2+ appears to bind was altered (WT: delta, 0.64 +/- 0.16, n = 6; H98D: delta, 0.16 +/- 0.03, n = 5, statistically different from WT; H98N: delta, 0.58 +/- 0.09, not statistically different from WT). Thus, the pore-neighbouring residue H98 contributes not only to the pH sensitivity of TASK1, but also to the structure of the conduction pathway.