Opposite effects of pH on open‐state probability and single channel conductance of Kir4.1 channels

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Abstract
1 A decrease in intracellular pH (pHi) inhibits whole-cell Kir4.1 currents. To understand channel biophysical properties underlying this inhibition, single channel Kir4.1 currents were studied in inside-out patches using symmetric concentrations of K+ applied to each side of the plasma membrane. Under such conditions, inward rectifying currents were observed in about 2 of 3 patches. At pH 7.4, these currents showed a single channel conductance of 22 pS with a channel open-state probability (Popen) of ≈0.9. 2 The effects of intracellular protons on macroscopic Kir4.1 currents were examined in giant inside-out patches at various pH levels of internal solutions. Current amplitude increased with a modest acidification (pH 7.0 and 6.6), and decreased with further reductions in pHi. The Kir4.1 currents were completely suppressed at pH 5.4. These effects were fast and reversible. 3 Low pHi inhibited Popen and enhanced single channel conductance in a concentration-dependent manner with pK (midpoint pH value for channel inhibition) of 6.0 and 6.8, respectively. At pH 5.8, Popen was inhibited by 70 % and single channel conductance increased by 35 %. Washout brought both Popen and single channel conductance rapidly back to baseline levels. 4 Theoretical currents were calculated using percentage changes in Popen and single channel conductance at each pH level tested. The trajectory of these currents is very close to that of experimental currents recorded from giant patches. Thus, opposite effects of intracellular protons on Popen and single channel conductance are demonstrated, which are likely to result in changes of macroscopic Kir4.1 currents with low pH.