Inactivation of glibenclamide-sensitive K+ channels in Xenopus oocytes by various calmodulin antagonists.
In follicle-enclosed Xenopus oocytes, extracellular application of cromakalim (a K+ channel opener) or intracellular injection of cAMP induces the smooth outward K+ current which is inactivated by glibenclamide. We found that cromakalim- or cAMP-induced K+ currents in the oocytes were rapidly, reversibly and dose-dependently blocked by various drugs having a calmodulin antagonizing activity in common, namely, by a selective calmodulin antagonist (W-7), antipsychotics (trifluoperazine, chlorpromazine, haloperidol), an antidepressant (amitriptyline), a beta-adrenoceptor blocker (propranolol), a local anesthetic (lidocaine) and a calcium antagonist (prenylamine). W-7, trifluoperazine, chlorpromazine and prenylamine were relatively potent blockers. For example, IC50 values to block cromakalim (100 microM)-induced K+ currents were 12 microM for trifluoperazine and 16 microM for W-7, which were close to their IC50 values to inhibit Ca2+/calmodulin-dependent phosphodiesterase (an index of the potency of calmodulin antagonists). IC50 values to inhibit cAMP (20 pmol/oocyte)-induced K+ currents were 126 microM for prenylamine and 129 microM for chlorpromazine. The IC50 values of all drugs tested to block cromakalim or cAMP responses were significantly correlated with their calmodulin-antagonizing potencies. Isoproterenol-induced K+ currents in the oocytes were also dose-dependently inhibited by glibenclamide, W-7 and trifluoperazine. These results suggest the possibility that the activity of glibenclamide-sensitive K+ channels in follicle-enclosed oocytes are regulated by calmodulin or a calmodulin-dependent process.
Sakuta
H
H
Department of Pharmacology, National Defense Medical College, Saitama, Japan.
Sekiguchi
M
M
Okamoto
K
K
Sakai
Y
Y
D000818:Animals; D001578:Benzopyrans / Q000494:pharmacology; D002147:Calmodulin / Q000037:antagonists & inhibitors*; D019806:Cromakalim; D000242:Cyclic AMP / Q000494:pharmacology; D005260:Female; D005905:Glyburide / Q000494:pharmacology*; D066298:In Vitro Techniques; D007545:Isoproterenol / Q000494:pharmacology; D009865:Oocytes / Q000187:drug effects / Q000378:metabolism*; D015221:Potassium Channels / Q000187:drug effects / Q000378:metabolism*; D011758:Pyrroles / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects; D014981:Xenopus
D001578:Benzopyrans; D002147:Calmodulin; D015221:Potassium Channels; D011758:Pyrroles; D019806:Cromakalim; D000242:Cyclic AMP; D007545:Isoproterenol; D005905:Glyburide