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

The effects of low intracellular pH (pHi 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 pHi 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 μM 1-ethyl-2-benzimidazolone was able to potentiate SK3 current to the same extent as at neutral pHi. We conclude that SK1–3 all are inhibited by low pHi. We suggest two components of inhibition: a [Ca2+]i-dependent component, likely involving the SK β-subunits calmodulin, and a voltage-dependent component, consistent with a pore-blocking effect. This pHi-dependent inhibition can be reversed pharmacologically.