Adaptive downregulation of a quinidine-sensitive cation conductance in renal principal cells of TWIK-1 knockout mice

TWIK-1, a member of the two-pore domain K+ channel family, is expressed in brain, kidney, and lung. The aim of this study was to examine the effect of loss of TWIK-1 on the renal cortical collecting duct. Ducts were isolated from wild-type and TWIK-1 knockout mice by enzyme digestion and whole-cell clamp obtained via the basolateral membrane. Current- and voltage-clamp approaches were used to examine K+ conductances. No difference was observed between intercalated cells from wild-type or knockout ducts. In contrast, knockout principal cells were hyperpolarized compared to wild-type cells and had a reduced membrane conductance. This was a consequence of a fall in a barium-insensitive, quinidine-sensitive conductance (G Quin). G Quin demonstrated outward rectification and had a relatively low K+ to Na+ selectivity ratio. Loss of G Quin would be expected to lead to the hyperpolarization observed in knockout ducts by increasing fractional K+ conductance and Na + uptake by the cell. Consistent with this hypothesis, knockout ducts had an increased diameter in comparison to wild-type ducts. These data suggest that G Quin contributes to the resting membrane potential in the cortical collecting duct and that a fall in G Quin could be an adaptive response in TWIK-1 knockout ducts. © 2006 Springer-Verlag.