RT Journal Article
SR Electronic
T1 Positive regulation by chloride channel blockers of IsK channels expressed in Xenopus oocytes.
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 750
OP 753
VO 46
IS 4
A1 A E Busch
A1 T Herzer
A1 C A Wagner
A1 F Schmidt
A1 G Raber
A1 S Waldegger
A1 F Lang
YR 1994
UL http://molpharm.aspetjournals.org/content/46/4/750.abstract
AB cRNA encoding the human IsK protein was injected into Xenopus oocytes and the induced IsK channels were investigated using the two-microelectrode voltage-clamp method. Niflumic acid, mefenamic acid, flufenamic acid, and 4,4'-diisothiocyanatostilbene-2,2'- disulfonic acid, which are commonly used in Xenopus oocytes to suppress endogenous Ca(2+)-activated Cl- channels, were tested for their effects on IsK channels. At low concentrations (10 microM) all compounds increased IsK amplitude and decreased the rate of IsK deactivation. At 100 microM these compounds further decreased the rate of IsK deactivation, resulting in persistent activation of IsK, similar to what has been previously described for the action of organic cross-linkers on IsK. However, at 100 microM niflumic acid and flufenamic acid decreased the time-dependent outward current, whereas 4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid and mefenamic acid caused an additional increase. When Cl- was completely substituted with gluconate, IsK had somewhat altered activation properties, but niflumic acid produced similar positive regulatory effects on IsK and shifted the voltage needed to evoke half-maximal IsK activation (V1/2) by about -20 mV. In summary, these compounds positively regulate IsK, presumably by stabilizing open IsK channels.