Subtype-specific, bi-component inhibition of SK channels by low internal pH.
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.
Danish Arrhythmia Research Center, Department of Medical Physiology, The Panum Institute, University of Copenhagen, Blegdamsvej 3, DK-2200 Copenhagen N, Denmark. torbenp@mfi.ku.dk
Torben
T
Peitersen
Charlotte
C
Hougaard
Thomas
T
Jespersen
Nanna K
NK
Jorgensen
Søren-Peter
SP
Olesen
Morten
M
Grunnet
D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D004553:Electric Conductivity; D006801:Humans; D006863:Hydrogen-Ion Concentration; D018408:Patch-Clamp Techniques; D051381:Rats; D051640:Small-Conductance Calcium-Activated Potassium Channels / Q000037:antagonists & inhibitors* / Q000145:classification
D001562:Benzimidazoles; D051640:Small-Conductance Calcium-Activated Potassium Channels; C102635:1-ethyl-2-benzimidazolinone; D002118:Calcium