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

• Published in: Biochemical and biophysical research communications Vol. 343; no. 3; pp. 943 - 949
• Main Authors: Peitersen, Torben, Hougaard, Charlotte, Jespersen, Thomas, Jorgensen, Nanna K., Olesen, Søren-Peter, Grunnet, Morten
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 12.05.2006
• Subjects: Animals; Benzimidazoles - pharmacology; Ca 2+-activated; Calcium - metabolism; Calmodulin; Cell Line; Electric Conductivity; Human; Humans; Hydrogen-Ion Concentration; Modulation; Patch-Clamp Techniques; Rat; Rats; SK1; SK2; SK3; Small conductance; Small-Conductance Calcium-Activated Potassium Channels - antagonists & inhibitors; Small-Conductance Calcium-Activated Potassium Channels - classification; Human; Ca 2+-activated; Rat; Modulation; Small conductance; SK1; pH; SK3; SK2; Calmodulin
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/j.bbrc.2006.03.026

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.