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Kir channels display voltage-dependent block by cytosolic cations such as Mg 2+  and polyamines that causes inward rectification. In fact, cations can regulate K channel activity from both the extracellular and intracellular sides. Previous studies have provided insight into the up-regulation of Kir channel activity by extracellular K +  concentration. In contrast, extracellular Mg 2+  has been found to reduce the amplitude of the single-channel current at milimolar concentrations. However, little is known about the molecular mechanism of Kir channel blockade by external Mg 2+  and the relationship between the Mg 2+  blockade and activity potentiation by permeant K +  ions. In this study, we applied an interactive approach between theory and experiment. Electrophysiological recordings on Kir2.2 and its mutants were performed by heterologous expression in  Xenopus laevis  oocytes. Our results confirmed that extracellular Mg 2+  could reduce heterologously expressed WT Kir2.2 currents in a voltage dependent manner. The kinetics of inhibition and recovery of Mg 2+  exhibit a 3∼4s time constant. Molecular dynamics simulation results revealed a Mg 2+  binding site located at the extracellular mouth of Kir2.2 that showed voltage-dependent Mg 2+  binding. The mutants, G119D, Q126E and H128D, increased the number of permeant K +  ions and reduced the voltage-dependent blockade of Kir2.2 by extracellular Mg 2+ .

Lack of Negatively Charged Residues at the External Mouth of Kir2.2 Channels Enable the Voltage-Dependent Block by External Mg2+