Subtype-specific, bi-component inhibition of SK channels by low internal pH

Abstract The effects of low intracellular pH (pH i 6.4) on cloned small-conductance Ca 2+ -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 Ca 2+ [Ca 2+ ] 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 Ca 2+ , the inhibition was abolished for SK1–3 channels at negative potentials, indicating a [Ca 2+ ] i -dependent mode of inhibition. Application of 50 μM 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 [Ca 2+ ] i -dependent component, likely involving the SK β-subunits calmodulin, and a voltage-dependent component, consistent with a pore-blocking effect. This pH i -dependent inhibition can be reversed pharmacologically.