Direct inhibition of inositol-1,4,5-trisphosphate-induced Ca2+ release from brain microsomes by K+ channel blockers.
Tetraethylammonium and 9-tetraethylammonium have previously been reported to inhibit inositol-1,4,5-trisphosphate (IP3)-induced Ca2+ release from brain microsomes, purportedly by blocking potassium channels [Biochem. J. 258:617-620 (1988)]. The effects of these and other K+ channel blockers have been studied here in greater detail using a spectrophotometric assay for Ca2+ movements into and out of canine brain microsomes. IP3-induced Ca2+ release was inhibited by substitution of K+ in the medium with nominally impermeant cations or by addition of most of the K+ channel blockers tested. Nevertheless, addition of valinomycin to the medium (to provide an alternative pathway for counter-ion K+ movements) failed to alleviate the inhibition of IP3-induced Ca2+ release caused by K+ channel blockers. To determine whether these substances act by inhibition of IP3 binding or by direct interaction with the Ca2+ channel of the internal store that promotes IP3-induced Ca2+ release, their effect on [3H]IP3 binding was investigated. None of the K+ channel blockers tested inhibited [3H]IP3 binding. Nearly all the K+ channel blockers appear to interact directly with a Ca2+ channel of the intracellular stores or perhaps interfere with its coupling to the IP3 receptor. Because of their multiplicity of actions, these substances cannot be presumed to be either selective K+ channel blockers or selective inhibitors of IP3-induced Ca2+ release from internal stores. Three of them were even found to partially inhibit valinomycin-stimulated 86Rb uptake into liposomes.
Palade
P
P
Department of Physiology and Biophysics, University of Texas Medical Branch, Galveston 77550.
Dettbarn
C
C
Volpe
P
P
Alderson
B
B
Otero
A S
AS
D015761:4-Aminopyridine / Q000494:pharmacology; D000585:Aminacrine / Q000494:pharmacology; D000818:Animals; D001464:Barium / Q000494:pharmacology; D001921:Brain / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism*; D004285:Dogs; D066298:In Vitro Techniques; D015544:Inositol 1,4,5-Trisphosphate / Q000494:pharmacology*; D008861:Microsomes / Q000378:metabolism; D015221:Potassium Channels / Q000187:drug effects*; D011803:Quinine / Q000494:pharmacology; D013757:Tetraethylammonium Compounds / Q000494:pharmacology
D015221:Potassium Channels; D013757:Tetraethylammonium Compounds; D001464:Barium; D000585:Aminacrine; D015544:Inositol 1,4,5-Trisphosphate; D011803:Quinine; D015761:4-Aminopyridine; D002118:Calcium