THE EFFECTS OF TETRAHEXYL AMMONIUM CATIONS (THA+) ON INOSITOL 1,4,5-TRISPHOSPHATE-INDUCED CALCIUM-RELEASE FROM PORCINE CEREBELLAR MICROSOMES - THA+ CAN INDUCE CALCIUM-RELEASE SELECTIVELY FROM THE INSP3-SENSITIVE CALCIUM STORES

In this study we show that the potassium-channel blocker tetrahexyl ammonium chloride (THA+) is able to inhibit inositol 1,4,5-trisphosphate (InsP3)-induced calcium release in an apparently biphasic fashion with a IC50 of 3 muM. This inhibition was not alleviated by valinomycin and, therefore, is not consistent with the blocking of K+ counter-ion movement, an observation initially made by Palade et al. (Palade, P., Dettbarn, C., Volpe, P., Alderson, B. and Otero, A.S (1989) Mol. Pharmacol. 36, 664-672). THA+ affected quantal calcium release by reducing the amount of calcium released by InsP3, but did not greatly affect the concentration of InsP3 required to cause half-maximal calcium release. THA+ did not affect the metabolism of InsP3 or its binding to porcine cerebellar microsomes. THA+ could also itself induce calcium release. At concentrations below 100 muM, THA+ appears to release Ca2+ selectively from the InsP3-sensitive calcium stores, since prior depletion of these stores with supramaximal doses of InsP3 abolishes this response. At higher THA+ concentrations (above 100 muM) Ca2+ is released non-selectively from all stores. THA+ has no effect on the Ca2+-ATPase activity at concentrations below 100 muM, indicating that selective THA+-induced Ca2+ release is not due to non-specific inhibition of the microsomal Ca2+ pumps and does not affect Ca2+ leakage. A number of pharmacological modulators of intracellular calcium channels were also tested on THA+-induced calcium release with little effect, except for spermidine which reduced this release by up to 50%. Our observations are consistent with the view that THA+, at concentrations below 100 muM, selectively releases calcium from the InsP3-sensitive calcium stores.