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Inward-rectifier potassium channels (Kir 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 Kir 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 KATP channels (Kir6.2 + 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 KATP as shown in experiments with other Kir channels. Systematic mutagenesis revealed a titratable C-terminal histidine residue (H216) in Kir6.2 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 KATP channels may represent a novel and direct link between excitation and intracellular pH.

Original publication

DOI

10.1093/emboj/18.4.847

Type

Journal article

Journal

EMBO J

Publication Date

15/02/1999

Volume

18

Pages

847 - 853

Keywords

ATP-Binding Cassette Transporters, Animals, Cells, Cultured, Hydrogen-Ion Concentration, Mice, Mutagenesis, Mutation, Myocardium, Patch-Clamp Techniques, Polyamines, Potassium Channels, Potassium Channels, Inwardly Rectifying, Receptors, Drug, Spermidine, Sulfonylurea Receptors