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Updated: Aug 9, 2026

High-throughput Screening for Small-molecule Modulators of Inward Rectifier Potassium Channels
Published on: January 27, 2013
Subtype-specific, bi-component inhibition of SK channels by low internal pH
Torben Peitersen1, Charlotte Hougaard, Thomas Jespersen
1Danish Arrhythmia Research Center, Department of Medical Physiology, The Panum Institute, University of Copenhagen, Blegdamsvej 3, DK-2200 Copenhagen N, Denmark. torbenp@mfi.ku.dk
Abstract:
The effects of low intracellular pH (pH(i) 6.4) on cloned small-conductance Ca2+-activated K+ channel currents of all three subtypes (SK1, SK2, and SK3) were investigated in HEK293 cells using the patch-clamp technique. In 400 nM internal Ca2+ [Ca2+]i, all subtypes were inhibited by pH(i) 6.4 in the order of sensitivity: SK1>SK3>SK2. The inhibition increased with the transmembrane voltage. In saturating internal Ca2+, the inhibition was abolished for SK1-3 channels at negative potentials, indicating a [Ca2+]i-dependent mode of inhibition. Application of 50 microM 1-ethyl-2-benzimidazolone was able to potentiate SK3 current to the same extent as at neutral pH(i). We conclude that SK1-3 all are inhibited by low pH(i). We suggest two components of inhibition: a [Ca2+]i-dependent component, likely involving the SK beta-subunits calmodulin, and a voltage-dependent component, consistent with a pore-blocking effect. This pH(i)-dependent inhibition can be reversed pharmacologically.
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