Inward rectification in K ATP channels: a pH switch in the pore

Inward‐rectifier potassium channels (K ir channels) stabilize the resting membrane potential and set a threshold for excitation in many types of cell. This function arises from voltage‐dependent rectification of these channels due to blockage by intracellular polyamines. In all K ir channels studied to date, the voltage‐dependence of rectification is either strong or weak. Here we show that in cardiac as well as in cloned K ATP channels (K ir 6.2 + sulfonylurea receptor) polyamine‐mediated rectification is not fixed but changes with intracellular pH in the physiological range: inward‐rectification is prominent at basic pH, while at acidic pH rectification is very weak. The pH–dependence of polyamine block is specific for K ATP as shown in experiments with other K ir channels. Systematic mutagenesis revealed a titratable C–terminal histidine residue (H216) in K ir 6.2 to be the structural determinant, and electrostatic interaction between this residue and polyamines was shown to be the molecular mechanism underlying pH‐dependent rectification. This pH‐dependent block of K ATP channels may represent a novel and direct link between excitation and intracellular pH.